Somatostatin modulators and uses thereof

ABSTRACT

Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.

RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.17/511,326 filed Oct. 26, 2021, which is a Continuation of U.S. patentapplication Ser. No. 16/877,947, filed May 19, 2020, now U.S. Pat. No.11,186,590, issued Nov. 30, 2021, which is a Continuation of Ser. No.16/572,921, filed Sep. 17, 2019, now U.S. Pat. No. 10,696,689, issuedJun. 30, 2020, which claims the benefit of U.S. Provisional PatentApplication No. 62/732,735 filed on Sep. 18, 2018, all of which areherein incorporated by reference in their entireties.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with government support under NS092231 awardedby the National Institutes of Health. The government has certain rightsin this invention.

FIELD OF THE INVENTION

Described herein are compounds that are somatostatin modulators, methodsof making such compounds, pharmaceutical compositions and medicamentscomprising such compounds, and methods of using such compounds in thetreatment of conditions, diseases, or disorders that would benefit frommodulating somatostatin activity.

BACKGROUND OF THE INVENTION

Somatostatin is a peptide hormone that regulates the endocrine systemand affects neurotransmission and cell proliferation via interactionwith G-protein-coupled somatostatin receptors and inhibition of therelease of numerous secondary hormones. Six subtype somatostatinreceptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3,SSTR4, SSTR5) and are encoded by five different somatostatin receptorgenes. Modulation of a particular subtype somatostatin receptor orcombination thereof, is attractive for the treatment of conditions,diseases, or disorders that would benefit from modulating somatostatinactivity.

SUMMARY OF THE INVENTION

Compounds described herein are somatostatin modulator compounds. In someembodiments, compounds described herein modulate one or more of thesubtype somatostatin receptor proteins. In some embodiments, compoundsdescribed herein modulate one subtype somatostatin receptor. In someembodiments, compounds described herein modulate SSTR2 somatostatinreceptor. Somatostatin peptide analogs, such as octreotide andpasireotide, formulated as depot injections, are routinely used tonormalize hormone levels for the treatment of Growth Hormone (GH)secreting adenomas, pancreatic neuroendocrine tumors, and carcinoidtumors. Unfortunately, these analogs are only effective in about half ofacromegalic patients with GH adenomas, and patients with carcinoidtumors frequently become resistant to therapy due to internalization anddesensitization of the SST2a receptor. In addition, these peptide drugsare extremely expensive and require frequent doctor's office visits forpainful injections that can lead to injection site reactions. Compoundsdescribed herein are molecules that are structurally different frompeptide analogs. The compounds described herein are somatostatinmodulators that are potent inhibitors of hormone secretion.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, or individual enantiomer thereof:

wherein:

-   -   R² is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R³ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form a substituted or unsubstituted 4-membered,        substituted or unsubstituted 5-membered or substituted or        unsubstituted 6-membered N-containing heterocyclic ring;    -   R⁵ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₂-C₄alkenyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R⁶ is substituted or unsubstituted C₁-C₄alkyl, substituted or        unsubstituted C₁-C₄fluoroalkyl, substituted or unsubstituted        C₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted monocyclic carbocycle, substituted or        unsubstituted monocyclic heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵,        —C(═O)N(R¹⁵)₂, —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR ¹⁵C(═O)R¹⁵, or        —C(R¹⁵)═N—OR¹⁵;    -   R⁷ is —CN;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   X¹ is N or C—R¹⁰;    -   R¹⁰ is hydrogen, F, Cl, Br, —CN, —N(R¹⁵)₂, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄fluoroalkyl,        substituted or unsubstituted C₁-C₄fluoroalkoxy, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R¹² is hydrogen, or substituted or unsubstituted C₁-C₆alkyl;    -   R¹³ is hydrogen, —N(R¹⁶)₂, —CN, —CO₂R¹⁴, —C(═O)N(R¹⁵)₂, —OR¹⁶,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆fluoroalkyl, or substituted or unsubstituted        C₁-C₆heteroalkyl;    -   or R¹² and R¹³ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        N-containing heterocyclic ring;    -   or R¹² and R¹⁶ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        N-containing heterocyclic ring;    -   each R¹⁴ is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle;    -   each R¹⁶ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁶ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ia), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ib), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, the compound of Formula (I) has the followingstructure of Formula (Ic), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, diastereomeric mixture, orindividual enantiomer thereof:

wherein:

-   -   R² is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   R³ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form a substituted or unsubstituted 5-membered        or substituted or unsubstituted 6-membered N-containing        heterocyclic ring;    -   R⁵ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   R⁶ is substituted or unsubstituted C₁-C₄alkyl, substituted or        unsubstituted C₁-C₄fluoroalkyl, substituted or unsubstituted        C₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted monocyclic carbocycle, substituted or        unsubstituted monocyclic heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵,        —C(═O)N(R¹⁵)₂, —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR¹⁵C(═O)R¹⁵, or        —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy; each R¹⁵        is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In one aspect, described herein is a compound of Formula (II), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, or individual enantiomer thereof:

wherein:

-   -   R¹ is —CN, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂, —S(═O)₂R¹⁵, or        —S(═O)₂N(R¹⁵)₂; R⁵ is hydrogen, substituted or unsubstituted        C₁-C₄alkyl, substituted or unsubstituted C₁-C₄fluoroalkyl,        substituted or unsubstituted C₂-C₄alkenyl, or substituted or        unsubstituted C₃-C₆cycloalkyl;    -   each R⁶ and R⁷ is independently halogen, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl,        substituted or unsubstituted C₂-C₄alkynyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        monocyclic carbocycle, substituted or unsubstituted monocyclic        heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,        —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR ¹⁵C(═O)R¹⁵, or —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   X¹ is N or C—R¹⁰;    -   R¹⁰ is hydrogen, F, Cl, Br, —CN, —N(R¹⁵)₂, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄fluoroalkyl,        substituted or unsubstituted C₁-C₄fluoroalkoxy, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R¹² is hydrogen, or substituted or unsubstituted C₁-C₆alkyl;    -   R¹³ is hydrogen, —N(R¹⁶)₂, —CN, —CO₂R¹⁴, —C(═O)N(R¹⁵)₂, —OR¹⁶,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆fluoroalkyl, or substituted or unsubstituted        C₁-C₆heteroalkyl;    -   or R¹² and R¹³ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        N-containing heterocyclic ring;    -   or R¹² and R¹⁶ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        N-containing heterocyclic ring;    -   each R¹⁴ is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle;    -   each R¹⁶ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁶ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In some embodiments, the compound of Formula (II) has the structure ofFormula (IIa), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, the compound of Formula (II) has the structure ofFormula (IIb), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, the compound of Formula (II) has the followingstructure of Formula (IIc), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, diastereomeric mixture, orindividual enantiomer thereof:

wherein:

-   -   R¹ is —CN, —CO₂R¹⁵, or —C(═O)N(R¹⁵)₂;    -   R⁵ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   each R⁶ and R⁷ is independently halogen, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl,        substituted or unsubstituted C₂-C₄alkynyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        monocyclic carbocycle, substituted or unsubstituted monocyclic        heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,        —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR¹⁵C(═O)R¹⁵, or —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In another aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, or individual enantiomer thereof:

wherein:

-   -   R¹ is —NR²R³, —OR², or R⁴;    -   R² is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R³ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form a substituted or unsubstituted 4-membered,        substituted or unsubstituted 5-membered or substituted or        unsubstituted 6-membered N-containing heterocyclic ring;    -   R⁴ is F, Cl, Br, —CN, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄alkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl,        —S(═O)₂—C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        —CO₂R¹⁵, —C(═O)N(R¹⁵)₂;    -   R⁵ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₂-C₄alkenyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   each R⁶ and R⁷ is independently halogen, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl,        substituted or unsubstituted C₂-C₄alkynyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        monocyclic carbocycle, substituted or unsubstituted monocyclic        heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,        —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR ¹⁵C(═O)R¹⁵, or —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   X¹ is N or C—R¹⁰;    -   R¹⁰ is hydrogen, F, Cl, Br, —CN, —N(R¹⁵)₂, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄fluoroalkyl,        substituted or unsubstituted C₁-C₄fluoroalkoxy, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R¹¹ is hydrogen or substituted or unsubstituted C₁-C₆alkyl;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In some embodiments, the compound of Formula (III) has the followingstructure of Formula (IIIa), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, diastereomeric mixture, orindividual enantiomer thereof:

wherein:

-   -   R¹ is —NR²R³, —OR², F, Cl, Br, —CN, C₁-C₄alkyl, or        C₁-C₄fluoroalkyl;    -   R² is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   R³ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form a substituted or unsubstituted 5-membered        or substituted or unsubstituted 6-membered N-containing        heterocyclic ring;    -   R⁵ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   each R⁶ and R⁷ is independently halogen, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl,        substituted or unsubstituted C₂-C₄alkynyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        monocyclic carbocycle, substituted or unsubstituted monocyclic        heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,        —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR ¹⁵C(═O)R¹⁵, or —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   R¹¹ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

Also described herein is a pharmaceutical composition comprising acompound described herein, or a pharmaceutically acceptable salt, orsolvate thereof, and at least one pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition is formulated foradministration to a mammal by intravenous administration, subcutaneousadministration, oral administration, inhalation, nasal administration,dermal administration, or ophthalmic administration. In someembodiments, the pharmaceutical composition is formulated foradministration to a mammal by oral administration. In some embodiments,the pharmaceutical composition is in the form of a tablet, a pill, acapsule, a liquid, a suspension, a gel, a dispersion, a solution, anemulsion, an ointment, or a lotion. In some embodiments, thepharmaceutical composition is in the form of a tablet, a pill, or acapsule.

Also described herein is a method of treating a disease or condition ina mammal that would benefit from the modulation of somatostatin receptoractivity comprising administering a small molecule non-peptidylcompound, or pharmaceutically acceptable salt, or solvate thereof, tothe mammal in need thereof. In some embodiments, the small moleculenon-peptidyl compound is orally administered. In some embodiments, thesmall molecule non-peptidyl compound is a compound as described herein,or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the small molecule non-peptidyl compound is a SSTR2modulator as described herein, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the disease or condition isacromegaly, a neuroendocrine tumor, an ophthalmic disease or condition,neuropathy, nephropathy, a respiratory disease or condition, cancer,pain, a neurodegenerative disease or condition, an inflammatory diseaseor condition, a psychiatric disease or condition, or combinationsthereof.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), Formula (II), orFormula (III), or a pharmaceutically acceptable salt thereof, is: (a)systemically administered to the mammal; and/or (b) administered orallyto the mammal; and/or (c) intravenously administered to the mammal;and/or (d) administered by inhalation; and/or (e) administered by nasaladministration; or and/or (f) administered by injection to the mammal;and/or (g) administered topically to the mammal; and/or (h) administeredby ophthalmic administration; and/or (i) administered rectally to themammal; and/or (j) administered non-systemically or locally to themammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which the compound is administered oncea day to the mammal or the compound is administered to the mammalmultiple times over the span of one day. In some embodiments, thecompound is administered on a continuous dosing schedule. In someembodiments, the compound is administered on a continuous daily dosingschedule.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are orally administeredto a human.

Articles of manufacture, which include packaging material, a compound ofFormula (I), Formula (II), or Formula (III), or a pharmaceuticallyacceptable salt thereof, within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable salt, tautomers, pharmaceutically acceptable N-oxide,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, is used for modulatingone or more subtype somatostatin receptor proteins, or for thetreatment, prevention or amelioration of one or more symptoms of adisease or condition that would benefit from modulating one or moresubtype somatostatin receptor proteins, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Somatostatin (SST), also known as somatotropin release inhibiting factor(SRIF) was initially isolated as a 14-amino acid peptide from ovinehypothalamii (Brazeau et al., Science 179, 77-79, 1973). An N-terminalextended 28-amino acid peptide with similar biological activity to14-amino acid somatostatin was subsequently isolated (Pradayrol et, al.,FEBS Letters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA,77, 6827-6831, 1980). SST is a regulatory peptide produced by severalcell types in response to other neuropeptides, neurotransmitters,hormones, cytokines, and growth factors. SST acts through both endocrineand paracrine pathways to affect its target cells. Many of these effectsare related to the inhibition of secretion of other hormones, mostnotably growth hormone (GH). They are produced by a wide variety of celltypes in the central nervous system (CNS) and gut and have multiplefunctions including modulation of secretion of growth hormone (GH),insulin, glucagon, as well as many other hormones that areanti-proliferative.

These pleotropic actions of somatostatins are mediated by sixsomatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4,SSTR5). The six somatostatin receptor proteins are encoded by fivedifferent somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16,427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405,1997). All the receptors are members of the class-A subgroup of the GPCRsuperfamily. SST2a receptor is the most widely expressed subtype inhuman tumors and is the dominant receptor by which GH secretion issuppressed. Unless otherwise stated, the term SSTR2 means SSTR2a.

It is possible to selectively modulate any one of the somatostatinreceptor subtypes, or combination thereof. In some embodiments,selectively modulating any one of the somatostatin receptor subtypesrelative to the other somatostatin receptor subtypes reduces unwantedside effects in a variety of clinical applications.

For example, selective modulation of SSTR2 activity mediates theinhibition of growth hormone (GH) release from the anterior pituitaryand glucagon release from pancreas. SSTR2 is also implicated in manyother biological functions such as, but not limited to, cellproliferation, nociception, inflammation, and angiogenesis. In someembodiments, a selective SSTR2 modulator is used in the treatment ofacromegaly, neuroendocrine tumors, pain, neuropathies, nephropathies,and inflammation, as well as retinopathies resulting from aberrant bloodvessel growth. In some other embodiments, a selective SSTR2 modulator isused in the treatment of arthritis, pain, cancer, inflammatory boweldisease, irritable bowel syndrome, Crohn's disease, Cushing's disease,acute lung injury, acute respiratory distress syndrome, and ophthalmicdisorders such as age-related macular degeneration (AMD), diabeticretinopathy, diabetic macular edema, and Graves ophthalmology, amongothers.

In one aspect, compounds described herein are modulators of SSTR2. Insome embodiments, compounds described herein selectively modulate theactivity of SSTR2 relative to the other somatostatin receptors.

In some embodiments, compounds described here are amenable to oraladministration to a mammal in need of treatment with a somatostatinmodulator.

In some embodiments, somatostatin receptor modulators described hereinhave utility over a wide range of therapeutic applications. In someembodiments, somatostatin receptor modulators described herein are usedin the treatment of a variety of diseases or conditions such as, but notlimited to acromegaly, neuroendocrine tumors, retinopathies and otherophthalmic disorders, neuropathy, nephropathy, respiratory diseases,cancers, pain, neurodegenerative diseases, inflammatory diseases, aswell as psychiatric and neurodegenerative disorders. In someembodiments, somatostatin receptor modulators described herein are usedin the treatment of acromegaly in a mammal.

In some embodiments, somatostatin receptor modulators described hereininhibit the secretion of various hormones and trophic factors inmammals. In some embodiments, the compounds are used to suppress certainendocrine secretions, such as, but not limited to GH, insulin, glucagonand prolactin. The suppression of certain endocrine secretions is usefulin the treatment of disorders such as acromegaly; endocrine tumors suchas carcinoids, VIPomas, insulinomas and glucagonomas; or diabetes anddiabetes-related pathologies, including retinopathy, neuropathy andnephropathy. In some embodiments, somatostatin receptor modulatorsdescribed herein are used to suppress exocrine secretions in thepancreas, stomach and intestines, for the treatment of disorders such aspancreatitis, fistulas, bleeding ulcers and diarrhea associated withsuch diseases as AIDS or cholera. Disorders involving autocrine orparacrine secretions of trophic factors such as IGF-1 (as well as someendocrine factors) which may be treated by administration of thecompounds described herein include cancers of the breast, prostate, andlung (both small cell and non-small cell epidermoids), as well ashepatomas, neuroblastomas, colon and pancreatic adenocarcinomas (ductaltype), chondrosarcomas, and melanomas, diabetic retinopathy, andatherosclerosis associated with vascular grafts and restenosis followingangioplasty.

In some embodiments, somatostatin receptor modulators described hereinare used to suppress the mediators of neurogenic inflammation (e.g.substance P or the tachykinins), and may be used in the treatment ofrheumatoid arthritis; psoriasis; topical inflammation such as isassociated with sunburn, eczema, or other sources of itching;inflammatory bowel disease; irritable bowel syndrome; allergies,including asthma and other respiratory diseases In some otherembodiments, the somatostatin receptor modulators described hereinfunction as neuromodulators in the central nervous system and are usefulin the treatment of Alzheimer's disease and other forms of dementia,pain, and headaches. In some embodiments, somatostatin receptormodulators described herein provide cytoprotection in disordersinvolving the splanchnic blood flow, including cirrhosis and oesophagalvarices.

Compounds

Compounds of Formula (I), Formula (II), or Formula (III), includingpharmaceutically acceptable salts, prodrugs, active metabolites andpharmaceutically acceptable solvates thereof, are somatostatin receptormodulators. In some embodiments, the compounds of Formula (I), Formula(II), or Formula (III), including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are SSTR2 modulators. In some embodiments, the somatostatinreceptor modulators are somatostatin receptor agonists.

In some embodiments, compounds described herein are at least 2 times, atleast 3 times, at least 4 times, at least 5 times, at least 6 times, atleast 7 times, at least 8 times, at least 9 times, at least 10 times, atleast 15 times, at least 20 times, at least 30 times, at least 40 times,at least 50 times, at least 100 times, at least 200 times more selectiveat modulating SSTR2 activity than SSTR4 receptor activity. In someembodiments, the R¹ group of the compounds described herein confersselectivity for modulating SSTR2 activity.

In some embodiments, it is desirable that SSTR2 modulators haveincreased water solubility and reduced possibility to be BBB penetrableby increasing hydrogen bond donors. In some embodiments, the R¹ group ofthe compounds described herein reduced liability associated BBBpenetration. In some embodiments, the R¹ group of the compounds hereindescribed increased water solubility.

In some embodiments, it is desirable that SSTR2 modulators have reducedmetabolic instability. In some embodiments, the R¹ group of thecompounds herein described reduce metabolic instability in human livermicrosomes. In some embodiments, R¹ corresponds to —NR²R³ of Formula(I).

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, individual enantiomers thereof:

wherein:

-   -   R² is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R³ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form a substituted or unsubstituted 4-membered,        substituted or unsubstituted 5-membered or substituted or        unsubstituted 6-membered N-containing heterocyclic ring;    -   R⁵ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₂-C₄alkenyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R⁶ is substituted or unsubstituted C₁-C₄alkyl, substituted or        unsubstituted C₁-C₄fluoroalkyl, substituted or unsubstituted        C₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted monocyclic carbocycle, substituted or        unsubstituted monocyclic heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵,        —C(═O)N(R¹⁵)₂, —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR ¹⁵C(═O)R¹⁵, or        —C(R¹⁵)═N—OR¹⁵;    -   R⁷ is —CN;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   X¹ is N or C—R¹⁰;    -   R¹⁰ is hydrogen, F, Cl, Br, —CN, —N(R¹⁵)₂, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄fluoroalkyl,        substituted or unsubstituted C₁-C₄fluoroalkoxy, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R¹² is hydrogen, or substituted or unsubstituted C₁-C₆alkyl;    -   R¹³ is hydrogen, —N(R¹⁶)₂, —CN, —CO₂R¹⁴, —C(═O)N(R¹⁵)₂, —OR¹⁶,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆fluoroalkyl, or substituted or unsubstituted        C₁-C₆heteroalkyl;    -   or R¹² and R¹³ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        N-containing heterocyclic ring;    -   or R¹² and R¹⁶ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        N-containing heterocyclic ring;    -   each R¹⁴ is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle; and    -   R¹⁶ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁶ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments Xis C—R¹ or N. In other embodiments, X is C—R¹. In some embodiments, X isN.

In some embodiments, R¹² is hydrogen or substituted or unsubstitutedC₁-C₆alkyl. In some embodiments, R¹² is hydrogen. In some embodiments,R¹² is substituted or unsubstituted C₁-C₆alkyl.

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ia), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ia-1), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ib), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ib-1), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, R² is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, orC₃-C₆cycloalkyl; R³ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, orC₃-C₆cycloalkyl; or R² and R³ are taken together with the N atom towhich they are attached to form a substituted or unsubstituted5-membered or substituted or unsubstituted 6-membered N-containingheterocyclic ring. In some embodiments, R² is hydrogen, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),—C(CH₃)₃, —CH₂CH₂OH, or —CH₂CH₂OCH₃; R³ is hydrogen, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),—C(CH₃)₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CF₃; or R² and R³ are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted azetidinyl, substituted or unsubstitutedpyrrolidinyl, substituted or unsubstituted piperidinyl, substituted orunsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl,or substituted or unsubstituted piperazinyl. In some embodiments, R² ishydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CH₂OCF₃; R³ is hydrogen, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, or —CH₂CH₂OCF₃; or R² and R³ are taken together with the Natom to which they are attached to form substituted or unsubstitutedpyrrolidinyl, substituted or unsubstituted piperidinyl, substituted orunsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl,or substituted or unsubstituted piperazinyl. In some embodiments, R² ishydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, or—CH₂CH₂OCF₃; R³ is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CF₃,—CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CH₂OCF₃; or R² and R³ are taken togetherwith the N atom to which they are attached to form substituted orunsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl,substituted or unsubstituted morpholinyl, or substituted orunsubstituted piperazinyl. In some embodiments, R² is hydrogen, —CH₃,—CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CH₂OCF₃; R³ is hydrogen, —CH₃, —CH₂CF₃,—CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CH₂OCF₃; or R² and R³ are taken togetherwith the N atom to which they are attached to form substituted orunsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl orsubstituted or unsubstituted morpholinyl. In some embodiments, R² ishydrogen or —CH₃; and R³ is hydrogen or —CH₃.

In some embodiments, R⁵ is hydrogen, substituted or unsubstitutedC₁-C₄alkyl, substituted or unsubstituted C₁-C₄fluoroalkyl, orsubstituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments, R⁵ ishydrogen or substituted or unsubstituted C₁-C₄alkyl. In someembodiments, R⁵ is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃. In someembodiments, R⁵ is hydrogen.

In some embodiments, R⁶ is substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₁-C₄fluoroalkyl, substituted orunsubstituted C₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted monocyclic carbocycle, substituted or unsubstitutedmonocyclic heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,—C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, or —NR¹⁵C(═O)R¹⁵. In some embodiments, R⁶ issubstituted or unsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl, substitutedor unsubstituted C₂-C₄alkynyl, —CN, or —OR¹⁵. In some embodiments, R⁶ is—CH₃, —CF₃, —CH═CH₂, —C≡CH, —CN, —OH, —OCH₃, or —OCF₃. In someembodiments, R⁶ is —CH₃, —CF₃, —CN, —OCH₃, or —OCF₃. In someembodiments, R⁶ is —CH₃, —CN, —OCH₃, or —OCF₃. In some embodiments, R⁶is —OCH₃.

In some embodiments, each R⁸ and R⁹ is independently hydrogen, halogen,C₁-C₄alkyl, C₁-C₄fluoroalkyl, or C₁-C₄alkoxy. In some embodiments, eachR⁸ and R⁹ is independently hydrogen, F, Cl, Br, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),—C(CH₃)₃, —CH₂F, —CHF₂, —CH₂CF₃, —OCH₃, or —OCH₂CH₃. In someembodiments, each R⁸ and R⁹ is independently hydrogen, F, C₁, Br, —CH₃,—CH₂F, —CHF₂, —CH₂CF₃, or —OCH₃. In some embodiments, each R⁸ and R⁹ isindependently F, Cl, Br, —CH₃, —CH₂CH₃, or —OCH₃. In some embodiments,each R⁸ and R⁹ is independently F, Cl, —CH₃, or —OCH₃.

In some embodiments, R¹² is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or—CH(CH₃)₂; R¹³ is hydrogen, —N(R¹⁶)₂, —CN, —CO₂R¹⁴, —C(═O)N(R¹⁵)₂,—OR¹⁶, or substituted or unsubstituted C₁-C₆heteroalkyl; or R¹² and R¹³are taken together with the intervening atoms to which they are attachedto form a substituted or unsubstituted N-containing heterocyclic ring;or R¹² and R¹⁶ are taken together with the intervening atoms to whichthey are attached to form a substituted or unsubstituted N-containingheterocyclic ring; and each R¹⁶ is independently selected from hydrogen,substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R¹² ishydrogen, —CH₃, or —CH₂CH₃; R¹³ is hydrogen, —N(R¹⁶)₂, —CN, —CO₂R¹⁴,—C(═O)N(R¹⁵)₂, —OR¹⁶, or substituted or unsubstituted C₁-C₆heteroalkyl;or R¹² and R¹³ are taken together with the intervening atoms to whichthey are attached to form a substituted or unsubstituted N-containing6-membered heterocyclic ring; or R¹² and R¹⁶ are taken together with theintervening atoms to which they are attached to form a substituted orunsubstituted morpholinyl; and each R¹⁶ is independently selected fromhydrogen, substituted or unsubstituted C₁-C₆alkyl. In some embodiments,R¹² is hydrogen, —CH₃, or —CH₂CH₃; R¹³ is hydrogen, —OCH₃, —OCH₂CH₃, or—OCF₃; or R¹² and R¹³ are taken together with the intervening atoms towhich they are attached to form a substituted or unsubstitutedN-containing 6-membered heterocyclic ring; or R¹² and R¹⁶ are takentogether with the intervening atoms to which they are attached to form asubstituted or unsubstituted morpholinyl. In some embodiments, R¹² ishydrogen; and R¹³ is hydrogen.

In some embodiments, the compound of Formula (I), has the structure ofFormula (Ic), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

wherein:

-   -   R² is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   R³ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form a substituted or unsubstituted 5-membered        or substituted or unsubstituted 6-membered N-containing        heterocyclic ring;    -   R⁵ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   R⁶ is substituted or unsubstituted C₁-C₄alkyl, substituted or        unsubstituted C₁-C₄fluoroalkyl, substituted or unsubstituted        C₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted monocyclic carbocycle, substituted or        unsubstituted monocyclic heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵,        —C(═O)N(R¹⁵)₂, —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR¹⁵C(═O)R¹⁵, or        —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In some embodiments, R² is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CH₂OCF₃;R³ is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂,—CF₃, —CH₂CF₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CH₂OCF₃; or R² and R³ aretaken together with the N atom to which they are attached to formsubstituted or unsubstituted pyrrolidinyl, substituted or unsubstitutedpiperidinyl, substituted or unsubstituted morpholinyl, substituted orunsubstituted thiomorpholinyl, or substituted or unsubstitutedpiperazinyl; and R⁵ is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃. In someembodiments, R² is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or —CH(CH₃)₂; R³is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or —CH(CH₃)₂; or R² and R³ aretaken together with the N atom to which they are attached to formsubstituted or unsubstituted pyrrolidinyl, substituted or unsubstitutedpiperidinyl, substituted or unsubstituted morpholinyl, substituted orunsubstituted thiomorpholinyl, or substituted or unsubstitutedpiperazinyl; and R⁵ is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃. In someembodiments, R² is hydrogen or —CH₃; R³ is hydrogen or —CH₃; and R⁵ ishydrogen.

In some embodiments, R⁶ is substituted or unsubstituted C₁-C₄alkyl,substituted or unsubstituted C₁-C₄fluoroalkyl, substituted orunsubstituted C₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynyl,—CN, or —OR¹⁵; and each R⁸ and R⁹ is independently hydrogen, halogen,C₁-C₄alkyl, C₁-C₄fluoroalkyl, or C₁-C₄alkoxy. In some embodiments, R⁶ is—CH₃, —CF₃, —CH═CH₂, —C≡CH, —CN, —OH, —OCH₃, or —OCF₃; and each R⁸ andR⁹ is independently hydrogen, F, Cl, Br, —CH₃, —CH₂F, —CHF₂, —CH₂CF₃, orOCH₃. In some embodiments, R⁶ is —CH₃, —CF₃, —CN, —OCH₃, or —OCF₃; andeach R⁸ and R⁹ is independently F, Cl, Br, —CH₃, —CH₂CH₃, or —OCH₃. Insome embodiments, R⁶ is —CH₃, —CN, —OCH₃, or —OCF₃; and each R⁸ and R⁹is independently F, Cl, —CH₃, or —OCH₃.

In some embodiments, the compound of Formula (I) has the structure ofFormula (Ic-1), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

wherein the variables are as defined for formula (Ic).

In some embodiments, the compound of Formula (I) has the followingstructure, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, R², R³, R⁸, and R⁹ are as described in Table 1.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, the compound of Formula (I) could have thestructure of Formula (Id) or (Ie). Formula (Id) and Formula (Ie) aretautomers. Formula (Id) and Formula (Ie) should be considered asidentical structures even their names could be different:

Likewise, Formula (Ia) and Formula (Ia-1) are tautomers, Formula (Ib)and Formula (Ib-1) are tautomers, and Formula (Ic) and Formula (Ic-1)are tautomers.

Exemplary compounds described herein include the compounds described inthe following Table 1.

TABLE 1

Cpd No. R² R³ R⁸ R⁹ 1-1 H H 3-F 5-CH₃ 1-2 H H 3-F 5-Cl 1-3 CH₃ CH₃ 3-F5-CH₃

Compounds in Table 1 are named:

-   1-1:    2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile;-   1-2:    2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridin-3-yl]-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile;    and-   1-3:    2-[4-(4-aminopiperidin-1-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile.

In some embodiments, provided herein is a pharmaceutically acceptablesalt of a compound that is described in Table 1.

In another aspect, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, or individual enantiomer thereof:

wherein:

-   -   R¹ is —CN, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂, —S(═O)₂R¹⁵, or        —S(═O)₂N(R¹⁵)₂;    -   R⁵ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₂-C₄alkenyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   each R⁶ and R⁷ is independently halogen, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl,        substituted or unsubstituted C₂-C₄alkynyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        monocyclic carbocycle, substituted or unsubstituted monocyclic        heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,        —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR ¹⁵C(═O)R¹⁵, or —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   X¹ is N or C—R¹⁰;    -   R¹⁰ is hydrogen, F, Cl, Br, —CN, —N(R¹⁵)₂, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄fluoroalkyl,        substituted or unsubstituted C₁-C₄fluoroalkoxy, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R¹² is hydrogen, or substituted or unsubstituted C₁-C₆alkyl;    -   R¹³ is hydrogen, —N(R¹⁶)₂, —CN, —CO₂R¹⁴, —C(═O)N(R¹⁵)₂, —OR¹⁶,        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₁-C₆fluoroalkyl, or substituted or unsubstituted        C₁-C₆heteroalkyl;    -   or R¹² and R¹³ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        N-containing heterocyclic ring;    -   or R¹² and R¹⁶ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        N-containing heterocyclic ring;    -   each R¹⁴ is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle;    -   each R¹⁶ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁶ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In some embodiments, the compound of Formula (II) has the structure ofFormula (IIa), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, the compound of Formula (II) has the structure ofFormula (IIb), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, R¹ is —CN, —CO₂R¹⁵, or —C(═O)N(R¹⁵)₂. In someembodiments, each R¹⁵ is independently hydrogen or C₁-C₄alkyl.

In some embodiments, R⁵ is hydrogen, substituted or unsubstitutedC₁-C₄alkyl, substituted or unsubstituted C₁-C₄fluoroalkyl, orsubstituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments, R⁵ ishydrogen or substituted or unsubstituted C₁-C₄alkyl. In someembodiments, R⁵ is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃. In someembodiments, R⁵ is hydrogen.

In some embodiments, R⁶ is halogen, substituted or unsubstitutedC₁-C₄alkyl, substituted or unsubstituted C₁-C₄fluoroalkyl, substitutedor unsubstituted C₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynylsubstituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, substituted orunsubstituted monocyclic C₁-C₅heteroaryl, —CN, —OR¹⁵, —CO₂R¹⁵,—C(═O)N(R¹⁵)₂, —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR¹⁵C(═O)R¹⁵, or—C(R¹⁵)═N—OR¹⁵; and R⁷ is halogen, substituted or unsubstitutedC₁-C₄alkyl, substituted or unsubstituted C₁-C₄fluoroalkyl, substitutedor unsubstituted C₂-C₄alkenyl, substituted or unsubstitutedC₂-C₄alkynyl, substituted or unsubstituted C₁-C₆heteroalkyl, —CN, —OH,or —O-(substituted or unsubstituted C₁-C₄alkyl). In some embodiments, R⁶is F, Cl, Br, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂CO₂H,—CH₂CO₂CH₃, —CH₂CO₂CH₂CH₃, —CH₂C(═O)NH₂, —CH₂C(═O)NHCH₃,—CH₂C(═O)N(CH₃)₂, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂F, —CHF₂, —CF₃,—CH═CH₂, —C≡CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl,pyrrolidinyl, tetrazolyl, —CN, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CO₂H, —CO₂CH₃, —CO₂CH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃,—C(═O)N(CH₃)₂, —C(═O)NHOCH₃, —C(═O)N(CH₃)OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂,—NHC(═O)CH₃, —NCH₃C(═O)CH₃, —NHC(═O)OCH₃, —NCH₃C(═O)OCH₃, —CH═N—OH, or—CH═N—OCH₃; and R⁷ is F, Cl, Br, —CH₃, —CH₂CH₃, —CF₃, —CH═CH₂, —C≡CH,—CN, —OH, —OCH₃, —OCH₂CH₃, or —OCF₃. In some embodiments, each R⁶ and R⁷is independently substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₁-C₄fluoroalkyl, substituted or unsubstitutedC₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted monocycliccarbocycle, substituted or unsubstituted monocyclic heterocycle, —CN,—OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂, —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, or—NR¹⁵C(═O)R¹⁵. In some embodiments, each R⁶ and R⁷ is independentlysubstituted or unsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl, substitutedor unsubstituted C₂-C₄alkynyl, —CN, or —OR¹⁵. In some embodiments, eachR⁶ and R⁷ is independently F, Cl, —CH₃, —CF₃, —CH═CH₂, —C≡CH, —CN, —OH,—OCH₃, or —OCF₃. In some embodiments, each R⁶ and R⁷ is independently F,Cl, —CH₃, —CF₃, —CN, —OCH₃, or —OCF₃. In some embodiments, each R⁶ andR⁷ is independently F, Cl, —CN, or —OCH₃. In some embodiments, each R⁶and R⁷ is independently F, Cl, Br, —CH₃, —CF₃, —CN, —OH, —OCH₃, or—OCF₃. In some embodiments, each R⁶ and R⁷ is independently F, Cl, —CNor —OCH₃.

In some embodiments, each R⁸ and R⁹ is independently halogen,C₁-C₄alkyl, C₁-C₄fluoroalkyl, or C₁-C₄alkoxy. In some embodiments, eachR⁸ and R⁹ is independently F, Cl, Br, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃,—CH₂F, —CHF₂, —CH₂CF₃, —OCH₃, or —OCH₂CH₃. In some embodiments, each R⁸and R⁹ is independently hydrogen, F, Cl, Br, —CH₃, —OCH₃, —CH₂F, —CHF₂,or —CH₂CF₃. In some embodiments, each R⁸ and R⁹ is independently F, Cl,Br, —CH₃, or —OCH₃. In some embodiments, each R⁸ and R⁹ is independentlyF, Cl, —CH₃, or —OCH₃.

In some embodiments, R¹² is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or—CH(CH₃)₂; R¹³ is hydrogen, —N(R¹⁶)₂, —CN, —CO₂R¹⁴, —C(═O)N(R¹⁵)₂,—OR¹⁶, or substituted or unsubstituted C₁-C₆heteroalkyl; or R¹² and R¹³are taken together with the intervening atoms to which they are attachedto form a substituted or unsubstituted N-containing heterocyclic ring;or R¹² and R¹⁶ are taken together with the intervening atoms to whichthey are attached to form a substituted or unsubstituted N-containingheterocyclic ring; each R¹⁶ is independently selected from hydrogen,substituted or unsubstituted C₁-C₆alkyl.

In some embodiments, R¹² is hydrogen, —CH₃, or —CH₂CH₃; R¹³ is hydrogen,—N(R¹⁶)₂, —CN, —CO₂R¹⁴, —C(═O)N(R¹⁵)₂, —OR¹⁶, or substituted orunsubstituted C₁-C₆heteroalkyl; or R¹² and R¹³ are taken together withthe intervening atoms to which they are attached to form a substitutedor unsubstituted N-containing 6-membered heterocyclic ring; or R¹² andR¹⁶ are taken together with the intervening atoms to which they areattached to form a substituted or unsubstituted morpholinyl; and eachR¹⁶ is independently selected from hydrogen, substituted orunsubstituted C₁-C₆alkyl.

In some embodiments, R¹² is hydrogen, —CH₃, or —CH₂CH₃; R¹³ is hydrogen,—OCH₃, —OCH₂CH₃, or —OCF₃; or R¹² and R¹³ are taken together with theintervening atoms to which they are attached to form a substituted orunsubstituted N-containing 6-membered heterocyclic ring; or R¹² and R¹⁶are taken together with the intervening atoms to which they are attachedto form a substituted or unsubstituted morpholinyl.

In some embodiments, R¹² is hydrogen; and R¹³ is hydrogen

In some embodiments, the compound of Formula (II) has the structure ofFormula (IIc), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

wherein:

-   -   R¹ is —CN, —CO₂R¹⁵, or —C(═O)N(R¹⁵)₂;    -   R⁵ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   each R⁶ and R⁷ is independently halogen, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl,        substituted or unsubstituted C₂-C₄alkynyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        monocyclic carbocycle, substituted or unsubstituted monocyclic        heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,        —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR¹⁵C(═O)R¹⁵, or —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In some embodiments, R¹ is —CN, —CO₂CH₃, —CO₂CH₂CH₃, —C(═O)NH₂,—CONHCH₃, or —C(═O)N(CH₃)₂. In some embodiments, R¹ is —CO₂CH₃,—CO₂CH₂CH₃, —C(═O)NH₂, —CONHCH₃, or —C(═O)N(CH₃)₂. In some embodiments,R¹ is —CO₂CH₃, or —CO₂CH₂CH₃. In some embodiments, R¹ is —C(═O)NH₂,—CONHCH₃, or —C(═O)N(CH₃)₂.

In some embodiments, each R⁶ and R⁷ is independently halogen,substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl, substitutedor unsubstituted C₂-C₄alkynyl, —CN, or —OR¹⁵; and each R⁸ and R⁹ isindependently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, orC₁-C₄alkoxy. In some embodiments, each R⁶ and R⁷ is independently F, Cl,Br, —CH₃, —CF₃, —CN, —OH, —OCH₃, or —OCF₃. In some embodiments, each R⁶and R⁷ is independently F, Cl, —CN, or —OCH₃. In some embodiments, eachR⁸ and R⁹ is independently hydrogen, halogen, C₁-C₄alkyl,C₁-C₄fluoroalkyl, or C₁-C₄alkoxy. In some embodiments, each R⁸ and R⁹ isindependently hydrogen, F, Cl, Br, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃, —CH₂F, —CHF₂,—CH₂CF₃, —OCH₃, or —OCH₂CH₃. In some embodiments, each R⁸ and R⁹ isindependently hydrogen, F, Cl, —CH₃, or —OCH₃.

In some embodiments, the compound of Formula (II) has the structure ofFormula (IIc-1), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof.

wherein the variables are as defined for formula (IIc).

In some embodiments, the compound of Formula (II) has the followingstructure, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, R¹ is as described in Table 2.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, the compound of Formula (II) could have thestructure of Formula (IId) or (IIe). Formula (IId) and Formula (IIe) aretautomers. Formula (IId) and Formula (IIe) should be considered asidentical structures even their names could be different:

Likewise, Formula (IIc) and Formula (IIc-1) are tautomers.

Exemplary compounds described herein include the compounds described inthe following Table 2.

TABLE 2

Cpd No. R¹ 2-1 —CO₂CH₃ 2-2 —CN 2-3 —CONH₂ 2-4 —CONHCH₃

Compounds in Table 2 are named:

-   2-1: methyl    4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxylate;-   2-2:    4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carbonitrile;-   2-3:    4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxamide;-   2-4:    4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-N-methylpyridine-2-carboxamide.

In some embodiments, provided herein is a pharmaceutically acceptablesalt of a compound that is described in Table 2.

In another aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, or individual enantiomer thereof:

wherein:

-   -   R¹ is —NR²R³, —OR², or R⁴;    -   R² is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R³ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form a substituted or unsubstituted 4-membered,        substituted or unsubstituted 5-membered or substituted or        unsubstituted 6-membered N-containing heterocyclic ring;    -   R⁴ is F, Cl, Br, —CN, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₄alkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl,        —S(═O)₂—C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        —CO₂R¹⁵, —C(═O)N(R¹⁵)₂;    -   R⁵ is hydrogen, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₄fluoroalkyl, substituted or        unsubstituted C₂-C₄alkenyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   each R⁶ and R⁷ is independently halogen, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl,        substituted or unsubstituted C₂-C₄alkynyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        monocyclic carbocycle, substituted or unsubstituted monocyclic        heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,        —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR ¹⁵C(═O)R¹⁵, or —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   X¹ is N or C—R¹⁰;    -   R¹⁰ is hydrogen, F, Cl, Br, —CN, —N(R¹⁵)₂, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄alkoxy, substituted or unsubstituted C₁-C₄fluoroalkyl,        substituted or unsubstituted C₁-C₄fluoroalkoxy, substituted or        unsubstituted C₁-C₄heteroalkyl, or substituted or unsubstituted        C₃-C₆cycloalkyl;    -   R¹¹ is hydrogen or substituted or unsubstituted C₁-C₆alkyl;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In some embodiments, R¹ is —NR²R³. In some embodiments, R² is hydrogen,C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, or C₃-C₆cycloalkyl; R³is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, orC₃-C₆cycloalkyl; or R² and R³ are taken together with the N atom towhich they are attached to form a substituted or unsubstituted4-membered, substituted or unsubstituted 5-membered or substituted orunsubstituted 6-membered N-containing heterocyclic ring. In someembodiments, R² is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃, —CH₂CH₂OH,—CH₂CH₂OCH₃, or —CH₂CN; R³ is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃,—CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CN, or —CH₂CF₃; or R² and R³ are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted azetidinyl, substituted or unsubstitutedpyrrolidinyl, substituted or unsubstituted piperidinyl, substituted orunsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl,or substituted or unsubstituted piperazinyl.

In some embodiments, R³ is hydrogen. In some embodiments, R² is —CH₃.

In some embodiments, R¹ is —OR². In some embodiments, R² is hydrogen,—CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —C(CH₃)₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CN, —CH₂F,—CHF₂, —CF₃, or —CH₂CF₃.

In some embodiments, R¹ is R⁴; and R⁴ is F, Cl, Br, —CN, C₁-C₄alkyl,—SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, —S(═O)₂—C₁-C₄alkyl, C₁-C₄fluoroalkyl,—CO₂C₁-C₄alkyl, or —C(═O)N(R¹⁵)₂. In some embodiments, R⁴ is F, Cl, Br,—CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —C(CH₃)₃, —CH₂F, —CHF₂, —CF₃, or —CH₂CF₃;

In some embodiments, R¹ is —NR²R³, —OR², F, Cl, Br, —CN, C₁-C₄alkyl, orC₁-C₄fluoroalkyl.

In some embodiments, R⁵ is hydrogen or substituted or unsubstitutedC₁-C₄alkyl. In some embodiments, R⁵ is hydrogen.

In some embodiments, R⁶ is halogen, substituted or unsubstitutedC₁-C₄alkyl, substituted or unsubstituted C₁-C₄fluoroalkyl, substitutedor unsubstituted C₂-C₄alkenyl, substituted or unsubstituted C₂-C₄alkynylsubstituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, substituted orunsubstituted monocyclic C₁-C₅heteroaryl, —CN, —OR¹⁵, —CO₂R¹⁵,—C(═O)N(R¹⁵)₂, —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR¹⁵C(═O)R¹⁵, or—C(R¹⁵)═N—OR¹⁵; and R⁷ is halogen, substituted or unsubstitutedC₁-C₄alkyl, substituted or unsubstituted C₁-C₄fluoroalkyl, substitutedor unsubstituted C₂-C₄alkenyl, substituted or unsubstitutedC₂-C₄alkynyl, substituted or unsubstituted C₁-C₆heteroalkyl, —CN, —OH,or —O-(substituted or unsubstituted C₁-C₄alkyl). In some embodiments, R⁶is F, Cl, Br, —CH₃, —CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CH₂CN, —CH₂CO₂H,—CH₂CO₂CH₃, —CH₂CO₂CH₂CH₃, —CH₂C(═O)NH₂, —CH₂C(═O)NHCH₃,—CH₂C(═O)N(CH₃)₂, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂F, —CHF₂, —CF₃,—CH═CH₂, —C≡CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl,pyrrolidinyl, tetrazolyl, —CN, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OH,—OCH₂CN, —OCF₃, —CO₂H, —CO₂CH₃, —CO₂CH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃,—C(═O)N(CH₃)₂, —C(═O)NHOCH₃, —C(═O)N(CH₃)OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂,—NHC(═O)CH₃, —NCH₃C(═O)CH₃, —NHC(═O)OCH₃, —NCH₃C(═O)OCH₃, —CH═N—OH, or—CH═N—OCH₃; and R⁷ is F, Cl, Br, —CH₃, —CH₂CH₃, —CF₃, —CH═CH₂, —C≡CH,—CN, —OH, —OCH₃, —OCH₂CH₃, or —OCF₃. In some embodiments, each R⁶ and R⁷is independently F, Cl, Br, —CH₃, —CF₃, —CN, —OH, —OCH₃, or —OCF₃. Insome embodiments, each R⁶ and R⁷ is independently F, Cl, —CN, or —OCH₃.

In some embodiments, each R⁸ and R⁹ is independently hydrogen, halogen,C₁-C₄alkyl, C₁-C₄fluoroalkyl, or C₁-C₄alkoxy. In some embodiments, eachR⁸ and R⁹ is independently hydrogen, F, Cl, Br, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),—C(CH₃)₃, —CH₂F, —CHF₂, —CH₂CF₃, —OCH₃, or —OCH₂CH₃. In someembodiments, each R⁸ and R⁹ is independently hydrogen, F, Cl, —CH₃, or—OCH₃.

In some embodiments, R¹¹ is hydrogen or C₁-C₄alkyl. In some embodiments,R¹¹ is hydrogen.

In some embodiments, the compound of Formula (III) has the structure ofFormula (IIIa), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

wherein:

-   -   R¹ is —NR²R³, —OR², F, Cl, Br, —CN, C₁-C₄alkyl, or        C₁-C₄fluoroalkyl;    -   R² is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   R³ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form a substituted or unsubstituted 5-membered        or substituted or unsubstituted 6-membered N-containing        heterocyclic ring;    -   R⁵ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   each R⁶ and R⁷ is independently halogen, substituted or        unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl,        substituted or unsubstituted C₂-C₄alkynyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        monocyclic carbocycle, substituted or unsubstituted monocyclic        heterocycle, —CN, —OR¹⁵, —CO₂R¹⁵, —C(═O)N(R¹⁵)₂,        —C(═O)N(R¹⁵)OR¹⁵, —N(R¹⁵)₂, —NR ¹⁵C(═O)R¹⁵, or —C(R¹⁵)═N—OR¹⁵;    -   each R⁸ and R⁹ is independently hydrogen, halogen, substituted        or unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        —CN, —OH, or substituted or unsubstituted C₁-C₄alkoxy;    -   R¹¹ is hydrogen or substituted or unsubstituted C₁-C₄alkyl;    -   each R¹⁵ is independently selected from hydrogen, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,        substituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl,        substituted or unsubstituted phenyl, and substituted or        unsubstituted monocyclic heteroaryl;    -   or two R¹⁵ on the same N atom are taken together with the N atom        to which they are attached to form a substituted or        unsubstituted N-containing heterocycle.

In some embodiments, R² is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CH₂OCF₃;R³ is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂,—CF₃, —CH₂CF₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, or —CH₂CH₂OCF₃; or R² and R³ aretaken together with the N atom to which they are attached to formsubstituted or unsubstituted pyrrolidinyl, substituted or unsubstitutedpiperidinyl, substituted or unsubstituted morpholinyl, substituted orunsubstituted thiomorpholinyl, or substituted or unsubstitutedpiperazinyl; and R⁵ is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃. In someembodiments, R² is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or —CH(CH₃)₂; R³is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or —CH(CH₃)₂; or R² and R³ aretaken together with the N atom to which they are attached to formsubstituted or unsubstituted pyrrolidinyl, substituted or unsubstitutedpiperidinyl, substituted or unsubstituted morpholinyl, substituted orunsubstituted thiomorpholinyl, or substituted or unsubstitutedpiperazinyl; and R⁵ is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃. In someembodiments, R² is hydrogen or —CH₃; R³ is hydrogen; and R⁵ is hydrogen.

In some embodiments, each R⁶ and R⁷ is independently halogen,substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₁-C₄fluoroalkyl, substituted or unsubstituted C₂-C₄alkenyl, substitutedor unsubstituted C₂-C₄alkynyl, —CN, or —OR¹⁵; and each R⁸ and R⁹ isindependently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, orC₁-C₄alkoxy. In some embodiments, each R⁶ and R⁷ is independently F, Cl,—CH₃, —CF₃, —CH═CH₂, —C≡CH, —CN, —OH, —OCH₃, or —OCF₃; and each R⁸ andR⁹ is independently hydrogen, F, Cl, Br, —CH₃, —CH₂F, —CHF₂, —CH₂CF₃, or—OCH₃. In some embodiments, each R⁶ and R⁷ is independently F, Cl, —CH₃,—CF₃, —CN, —OCH₃, or —OCF₃; and each R⁸ and R⁹ is independentlyhydrogen, F, Cl, Br, —CH₃, or —OCH₃. In some embodiments, each R⁶ and R⁷is independently F, Cl, —CH₃, —CN, —OCH₃, or —OCF₃; and each R⁸ and R⁹is independently hydrogen, F, Cl, —CH₃, or —OCH₃.

In some embodiments, the compound of Formula (III) has the structure ofFormula (IIIa-1), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, diastereomeric mixture, orindividual enantiomer thereof:

wherein the variables are as defined for formula (IIIa).

In some embodiments, the compound of Formula (III) has the followingstructure, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, diastereomeric mixture, or individual enantiomerthereof:

In some embodiments, R^(a), R¹, R⁸, and R⁹ are as described in Table 3.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, the compound of Formula (III) could have thestructure of Formula (IIIb) or (IIIc). Formula (IIIb) and Formula (IIIc)are tautomers. Formula (IIIb) and Formula (IIIc) should be considered asidentical structures even their names could be different:

Likewise, Formula (IIIa) and Formula (IIIa-1) are tautomers.

Exemplary compounds described herein include the compounds described inthe following Table 3.

TABLE 3

Cpd No. R^(a) R² R⁸ R⁹ 3-1

—H 3-F 5-CH₃ 3-2

—H 3-F 5-F 3-3

—H 3-F 5-H 3-4

—H 3-F 5-OMe 3-5

—CH₃ 3-F 5-OMe 3-6

—CH₃ 3-F 5-F 3-7

—H 3-Cl 5-F 3-8

—H 3-F 5-OCH₃ 3-9

—H 3-F 5-H 3-10

—CH₃ 3-F 5-H 3-11

—H 3-F 5-H 3-12

—CH₃ 3-F 5-H 3-13

—CH₃ 3-Cl 5-F 3-14

—H 3-F 5-CH₃ 3-15

—CH₃ 3-F 5-CH₃ 3-16

—H 3-F 5-CH₃ 3-17

—H 3-Cl 5-F 3-18

—H 3-F 5-F 3-19

—H 3-F 5-F

Compounds in Table 3 are named:

-   3-1:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-amine;-   3-2:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3,5-difluorophenyl)pyridin-2-amine;-   3-3:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluorophenyl)pyridin-2-amine;-   3-4:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)pyridin-2-amine;-   3-5:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)-N-methylpyridin-2-amine;-   3-6:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3,5-difluorophenyl)-N-methylpyridin-2-amine;-   3-7:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(3-chloro-5-fluorophenyl)-3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)pyridin-2-amine;-   3-8:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)pyridin-2-amine;-   3-9:    4-[(4αS,8αS)-octahydro-H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluorophenyl)pyridin-2-amine:-   3-10:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluorophenyl)-N-methylpyridin-2-amine;-   3-11: 2-{4-[(4αS,    8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-2-amino-5-(3-fluorophenyl)pyridin-3-yl}-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile;-   3-12:    2-{4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(3-fluorophenyl)-2-(methylamino)pyridin-3-yl}-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile;-   3-13:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(3-chloro-5-fluorophenyl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-N-methylpyridin-2-amine;-   3-14:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-amine;-   3-15:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-N-methylpyridin-2-amine;-   3-16:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-amine;-   3-17:    4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(3-chloro-5-fluorophenyl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-2-amine;-   3-18:    2-{4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-2-amino-5-(3,5-difluorophenyl)pyridin-3-yl}-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile;-   3-19:    2-{4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-2-amino-5-(3,5-difluorophenyl)pyridin-3-yl}-4-fluoro-1H-1,3-benzodiazole-6-carbonitrile.

In some embodiments, provided herein is a pharmaceutically acceptablesalt of a compound that is described in Table 3.

In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial is administered to an individual without causing undesirablebiological effects or interacting in a deleterious manner with any ofthe components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Zrich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts typicallyare more soluble and more rapidly soluble in stomach and intestinaljuices than non-ionic species and so are useful in solid dosage forms.Furthermore, because their solubility often is a function of pH,selective dissolution in one or another part of the digestive tract ispossible and this capability can be manipulated as one aspect of delayedand sustained release behaviors. Also, because the salt-forming moleculecan be in equilibrium with a neutral form, passage through biologicalmembranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound of Formula (I), Formula (II), or Formula (III) withan acid. In some embodiments, the compound of Formula (I), Formula (II),or Formula (III) (i.e. free base form) is basic and is reacted with anorganic acid or an inorganic acid. Inorganic acids include, but are notlimited to, hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, nitric acid, and metaphosphoric acid. Organic acidsinclude, but are not limited to, 1-hydroxy-2-naphthoic acid;2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaricacid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid;adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid;benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capricacid (decanoic acid); caproic acid (hexanoic acid); caprylic acid(octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamicacid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonicacid; formic acid; fumaric acid; galactaric acid; gentisic acid;glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamicacid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuricacid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid;maleic acid; malic acid (−L); malonic acid; mandelic acid (DL);methanesulfonic acid; naphthalene-1,5-disulfonic acid;naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid;palmitic acid; pamoic acid; phosphoric acid; proprionic acid;pyroglutamic acid (−L); salicylic acid; sebacic acid; stearic acid;succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid;toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, a compound of Formula (I), Formula (II), or Formula(III) is prepared as a chloride salt, sulfate salt, bromide salt,mesylate salt, maleate salt, citrate salt or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound of Formula (I), Formula (II), or Formula (III) witha base. In some embodiments, the compound of Formula (I), Formula (II),or Formula (III) is acidic and is reacted with a base. In suchsituations, an acidic proton of the compound of Formula (I), Formula(II), or Formula (III) is replaced by a metal ion, e.g., lithium,sodium, potassium, magnesium, calcium, or an aluminum ion. In somecases, compounds described herein coordinate with an organic base, suchas, but not limited to, ethanolamine, diethanolamine, triethanolamine,tromethamine, meglumine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium hydroxide, lithiumhydroxide, and the like. In some embodiments, the compounds providedherein are prepared as a sodium salt, calcium salt, potassium salt,magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), or pharmaceutically acceptable salts ofcompounds having the structure of Formula (I), Formula (II), or Formula(III), as well as active metabolites of these compounds having the sametype of activity.

In some embodiments, sites on the organic radicals (e.g. alkyl groups,aromatic rings) of compounds of Formula (I), Formula (II), or Formula(III) are susceptible to various metabolic reactions. Incorporation ofappropriate substituents on the organic radicals will reduce, minimizeor eliminate this metabolic pathway. In specific embodiments, theappropriate substituent to decrease or eliminate the susceptibility ofthe aromatic ring to metabolic reactions is, by way of example only, ahalogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkylgroup.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine,phosphorus, such as, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ³²P and ³³P. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, the compounds of Formula (I), Formula (II), orFormula (III) possess one or more stereocenters and each stereocenterexists independently in either the R or S configuration. In someembodiments, the compound of Formula (I), Formula (II), or Formula (III)exists in the R configuration. In some embodiments, the compound ofFormula (I), Formula (II), or Formula (III) exists in the Sconfiguration. The compounds presented herein include alldiastereomeric, individual enantiomers, atropisomers, and epimeric formsas well as the appropriate mixtures thereof. The compounds and methodsprovided herein include all cis, trans, syn, anti, entgegen (E), andzusammen (Z) isomers as well as the appropriate mixtures thereof.

Individual stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns or the separation of diastereomers byeither non-chiral or chiral chromatographic columns or crystallizationand recrystallization in a proper solvent or a mixture of solvents. Incertain embodiments, compounds of Formula (I), Formula (II), or Formula(III) are prepared as their individual stereoisomers by reacting aracemic mixture of the compound with an optically active resolving agentto form a pair of diastereoisomeric compounds/salts, separating thediastereomers and recovering the optically pure individual enantiomers.In some embodiments, resolution of individual enantiomers is carried outusing covalent diastereomeric derivatives of the compounds describedherein. In another embodiment, diastereomers are separated byseparation/resolution techniques based upon differences in solubility.In other embodiments, separation of stereoisomers is performed bychromatography or by the forming diastereomeric salts and separation byrecrystallization, or chromatography, or any combination thereof. JeanJacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates andResolutions”, John Wiley And Sons, Inc., 1981. In some embodiments,stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug. Theyare, for instance, bioavailable by oral administration whereas theparent is not. Further or alternatively, the prodrug also has improvedsolubility in pharmaceutical compositions over the parent drug. In someembodiments, the design of a prodrug increases the effective watersolubility. An example, without limitation, of a prodrug is a compounddescribed herein, which is administered as an ester (the “prodrug”) butthen is metabolically hydrolyzed to provide the active entity. A furtherexample of a prodrug is a short peptide (polyaminoacid) bonded to anacid group where the peptide is metabolized to reveal the active moiety.In certain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternaryderivatives of tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates, phosphate esters, and sulfonate esters. See for exampleDesign of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method inEnzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396;Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of DrugDesign and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991,Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review,1992, 8, 1-38, each of which is incorporated herein by reference. Insome embodiments, a hydroxyl group in the compounds disclosed herein isused to form a prodrug, wherein the hydroxyl group is incorporated intoan acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, arylester, phosphate ester, sugar ester, ether, and the like. In someembodiments, a hydroxyl group in the compounds disclosed herein is aprodrug wherein the hydroxyl is then metabolized in vivo to provide acarboxylic acid group. In some embodiments, a carboxyl group is used toprovide an ester or amide (i.e. the prodrug), which is then metabolizedin vivo to provide a carboxylic acid group. In some embodiments,compounds described herein are prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I), Formula (II),or Formula (III) as set forth herein are included within the scope ofthe claims. In some cases, some of the herein-described compounds is aprodrug for another derivative or active compound.

In some embodiments, any one of the hydroxyl group(s), amino group(s)and/or carboxylic acid group(s) are functionalized in a suitable mannerto provide a prodrug moiety. In some embodiments, the prodrug moiety isas described above.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulfhydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

Synthesis of Compounds

Compounds of Formula (I), Formula (II), or Formula (III) describedherein are synthesized using standard synthetic techniques or usingmethods known in the art in combination with methods described herein.

Unless otherwise indicated, conventional methods of mass spectroscopy,NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniquesand pharmacology are employed.

Compounds are prepared using standard organic chemistry techniques suchas those described in, for example, March's Advanced Organic Chemistry,6^(th) Edition, John Wiley and Sons, Inc. Alternative reactionconditions for the synthetic transformations described herein may beemployed such as variation of solvent, reaction temperature, reactiontime, as well as different chemical reagents and other reactionconditions.

In some other embodiments, compounds described herein are prepared asdescribed in Scheme A.

Nucleophilic substitution of I by 4-Boc aminopiperidine affordedintermediate II. Compound II was treated with NBS to yield intermediateIII which was subsequently converted to intermediate IV by anorganometallic coupling reaction such as Suzuki-Miyaura reaction withArR⁸R⁹B(OH)₂. Benzimidazole formation between IV and corresponding1,2-diaminobenzenes was achieved by heating in wet DMF or NMP or DMSO orother solvent with or without Na₂S₂O₅ under atmospheric oxygen.Subsequent removal of a protecting group using appropriate deprotectionmethods yielded the compound V. In some other embodiments, compoundsdescribed herein are prepared as described in Scheme B.

The amino pyridine IV was alkylated to VI using the corresponding alkylhalide (R²—X) and a base. Benzimidazole formation and deprotection by asimilar manner described in Scheme A gave compound VII. N-alkylation ofVIII with an alkyl halide (R⁵—X) can be regioselectively achieved anddeprotection of the amino protection group also produced compound IX.

In some other embodiments, compounds described herein are prepared asdescribed in Scheme C.

Regioselective bromination of I with NBS afforded intermediate X. Theconversion of X to XXIII was completed by the similar manner describedin Scheme A.

In some other embodiments, compounds described herein are prepared asdescribed in Scheme D.

Compound XIV reacted with an amine to form XV. Bromination of XV andfollowed by Suzuki coupling reaction resulted in XVI, which was heatedwith a aryl-diamine to produce XVII. A carbon monoxide insertion in thepresence of an alcohol led to formation of XVIII, which can be convertedto XIX by ammonia, further dehydralation to afford XX. Deprotection ofVIII or XIX or XX yielded XXI.

Certain Terminology

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₆” indicates that there are oneto six carbon atoms in the moiety, i.e. groups containing 1 carbon atom,2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated. In some embodiments, an alkyl is a C₁-C₆alkyl. In one aspectthe alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, or t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers to a divalent alkyl radical. Any of the abovementioned monovalent alkyl groups may be an alkylene by abstraction of asecond hydrogen atom from the alkyl. In some embodiments, an alkelene isa C₁-C₆alkylene. In other embodiments, an alkylene is a C₁-C₄alkylene.Typical alkylene groups include, but are not limited to, —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like. In someembodiments, an alkylene is —CH₂—.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where x is0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom isreplaced by a hydroxyl. In some embodiments, a hydroxyalkyl is aC₁-C₄hydroxyalkyl. Typical hydroxyalkyl groups include, but are notlimited to, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, and thelike.

An “aminoalkyl” refers to an alkyl in which one hydrogen atom isreplaced by an amino. In some embodiments, aminoalkyl is aC₁-C₄aminoalkyl. Typical aminoalkyl groups include, but are not limitedto, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂, and the like.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. In some embodiments, an alkenyl isselected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl,pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenylgroup include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃, and—CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl. In someembodiments, an alkynyl is selected from ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like. Non-limiting examples of an alkynylgroup include —C≡CH, —C≡CCH₃—C≡CCH₂CH₃, —CH₂C≡CH.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “aromatic” refers to a planar ring having a delocalizedit-electron system containing 4n+2π it electrons, where n is an integer.The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g.,phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”)groups (e.g., pyridine). The term includes monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of thetwo rings of a bicyclic carbocycle is aromatic. In some embodiments,both rings of a bicyclic carbocycle are aromatic. Carbocycles includearyls and cycloalkyls.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, ortetrahyodronaphthyl. In some embodiments, an aryl is a C₆-C₁₀aryl.Depending on the structure, an aryl group is a monoradical or adiradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls arespirocyclic or bridged compounds. In some embodiments, cycloalkyls areoptionally fused with an aromatic ring, and the point of attachment isat a carbon that is not an aromatic ring carbon atom. Cycloalkyl groupsinclude groups having from 3 to 10 ring atoms. In some embodiments,cycloalkyl groups are selected from among cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Insome embodiments, a cycloalkyl is a C₃-C₆cycloalkyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, orbromo.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings containing one tofour heteroatoms in the ring(s), where each heteroatom in the ring(s) isselected from O, S and N, wherein each heterocyclic group has from 3 to10 atoms in its ring system, and with the proviso that any ring does notcontain two adjacent O or S atoms. Non-aromatic heterocyclic groups(also known as heterocycloalkyls) include rings having 3 to 10 atoms inits ring system and aromatic heterocyclic groups include rings having 5to 10 atoms in its ring system. The heterocyclic groups includebenzo-fused ring systems. Examples of non-aromatic heterocyclic groupsare pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl,indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclcic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine,indole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

A “heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. In someembodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. Insome embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl,pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl,imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heterocycloalkylalso includes all ring forms of the carbohydrates, including but notlimited to the monosaccharides, the disaccharides and theoligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkylcontains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,—S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,—CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments, substitutedgroups are substituted with one or two of the preceding groups. In someembodiments, an optional substituent on an aliphatic carbon atom(acyclic or cyclic) includes oxo (═O).

In some embodiments, each substituted alkyl, substituted fluoroalkyl,substituted heteroalkyl, substituted carbocycle, and substitutedheterocycle is substituted with one or more R^(s) groups independentlyselected from the group consisting of halogen, C₁-C₆alkyl, monocycliccarbocycle, monocyclic heterocycle, —CN, —OR²⁰, —CO₂R²⁰, —C(═O)N(R²⁰)₂,—N(R²⁰)₂, —NR²⁰C(═O)R²¹, —SR²⁰, —S(═O)R²¹, —SO₂R²¹, or —SO₂N(R²⁰)₂; eachR²⁰ is independently selected from hydrogen, C₁-C₆alkyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl,benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R²⁰groups are taken together with the N atom to which they are attached toform a N-containing heterocycle; each R²¹ is independently selected fromC₁-C₆alkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl,phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an agonist.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), Formula (II), or Formula(III), or a pharmaceutically acceptable salt thereof, and a co-agent,are both administered to a patient simultaneously in the form of asingle entity or dosage. The term “non-fixed combination” means that theactive ingredients, e.g. a compound of Formula (I), Formula (II), orFormula (III), or a pharmaceutically acceptable salt thereof, and aco-agent, are administered to a patient as separate entities eithersimultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The terms “article of manufacture” and “kit” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

In some embodiments, the compounds described herein are administeredeither alone or in combination with pharmaceutically acceptablecarriers, excipients or diluents, in a pharmaceutical composition.Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only, compounds describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant. The administrationcan also be by direct injection at the site of a diseased tissue ororgan.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules, cachetsor tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, theactive ingredient is presented as a bolus, electuary or paste.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In some embodiments, pharmaceutical compositions are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parenteral administration includeaqueous and non-aqueous (oily) sterile injection solutions of the activecompounds which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

Pharmaceutical compositions may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical compositions may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.0010% to 10% w/w, for instance from 10% to 2% byweight of the formulation.

Pharmaceutical compositions for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds of Formula (I), Formula (II), orFormula (III), or a pharmaceutically acceptable salt thereof, are usedin the preparation of medicaments for the treatment of diseases orconditions in a mammal that would benefit from modulation ofsomatostatin activity. Methods for treating any of the diseases orconditions described herein in a mammal in need of such treatment,involves administration of pharmaceutical compositions that include atleast one compound of Formula (I), Formula (II), or Formula (III) or apharmaceutically acceptable salt, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said mammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound of Formula (I), Formula (II), orFormula (III), or a pharmaceutically acceptable salt thereof, in orderto prevent a return of the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-2000 mg per day. In one embodiment,the desired dose is conveniently presented in a single dose or individed doses administered simultaneously or at appropriate intervals,for example as two, three, four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compound ofFormula (I), Formula (II), or Formula (III), or a pharmaceuticallyacceptable salt thereof, described herein are from about 0.01 to about50 mg/kg per body weight. In some embodiments, the daily dosage or theamount of active in the dosage form are lower or higher than the rangesindicated herein, based on a number of variables in regard to anindividual treatment regime. In various embodiments, the daily and unitdosages are altered depending on a number of variables including, butnot limited to, the activity of the compound used, the disease orcondition to be treated, the mode of administration, the requirements ofthe individual subject, the severity of the disease or condition beingtreated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), Formula (II), orFormula (III), or a pharmaceutically acceptable salt thereof, is: (a)systemically administered to the mammal; and/or (b) administered orallyto the mammal; and/or (c) intravenously administered to the mammal;and/or (d) administered by injection to the mammal; and/or (e)administered topically to the mammal; and/or (f) administerednon-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I), Formula (II), or Formula (III), or apharmaceutically acceptable salt thereof, in combination with one ormore other therapeutic agents.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

In one specific embodiment, a compound of Formula (I), Formula (II), orFormula (III), or a pharmaceutically acceptable salt thereof, isco-administered with a second therapeutic agent, wherein the compound ofFormula (I), Formula (II), or Formula (III), or a pharmaceuticallyacceptable salt thereof, and the second therapeutic agent modulatedifferent aspects of the disease, disorder or condition being treated,thereby providing a greater overall benefit than administration ofeither therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient is simply beadditive of the two therapeutic agents or the patient experiences asynergistic benefit.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds of Formula (I), Formula (II), or Formula (III), or apharmaceutically acceptable salt thereof, as well as combinationtherapies, are administered before, during or after the occurrence of adisease or condition, and the timing of administering the compositioncontaining a compound varies. Thus, in one embodiment, the compoundsdescribed herein are used as a prophylactic and are administeredcontinuously to subjects with a propensity to develop conditions ordiseases in order to prevent the occurrence of the disease or condition.In another embodiment, the compounds and compositions are administeredto a subject during or as soon as possible after the onset of thesymptoms. In specific embodiments, a compound described herein isadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease. In some embodiments, the lengthrequired for treatment varies, and the treatment length is adjusted tosuit the specific needs of each subject.

EXAMPLES

As used above, and throughout the description of the invention, thefollowing abbreviations, unless otherwise indicated, shall be understoodto have the following meanings:

Abbreviations

-   AcOH: acetic acid;-   ACN or MeCN or CH₃CN: acetonitrile;-   DCM: dichloromethane-   DMF: dimethylformamide;-   DMSO: dimethyl sulfoxide;-   LC-MS: liquid chromatography-mass spectrometry;-   MS: mass spectrometry;-   NBS: N-bromosuccinimide;-   NMP: N-Methyl-2-pyrrolidone;-   NMR: nuclear magnetic resonance;-   Prep-HPLC: preparative high performance liquid chromatography;-   RP-HPLC: reverse phase high performance liquid chromatography;-   SST: somatostatin;-   SSTR: somatostatin receptor;-   TEA: triethylamine;-   TFA: trifluoroacetic acid;-   TFAA: trifluoroacetic anhydride;-   ° C.: degree Celsius;-   equiv: equivalent(s);-   g: gram(s);-   h or hr: hour;-   hrs: hours;-   mg: milligram(s);-   MHz: megahertz;-   min: minute;-   mL or ml: milliliter(s);-   mm: millimetre(s);-   mmol: millimole(s);-   μm or um: micrometre(s);-   nm: nanometre:-   rt: room temperature;-   CHCl₃: chloroform;-   CO: carbon monooxide;-   H₂O: water;-   HBF₄: tetrafluoroboric acid;-   HCl: hydrochloric acid or hydrochloride;-   K₂CO₃: potassium carbonate;-   KOH: potassium hydroxide;-   K₃PO₄: tripotassium phosphate;-   MeOH: methanol;-   Me₂NH: dimethylamine-   N₂: nitrogen gas;-   NH₃: ammonia-   Na₂SO₄: sodium sulfate;-   Na₂S₂O₅: sodium metabisulfite;-   P(t-Bu)₃: tri-tert-buytlphosphine;-   Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0);-   Pd(PPh₃)₂Cl₂: bis(triphenylphosphine)palladium(II) dichloride;-   Pd(dppf)Cl₂: [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)    dichloride;-   Xantphos—4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;-   Zn(CN)₂: zinc cyanide.

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Example 1:2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile(1-1)

Step 1-1, preparation of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene: amixture of 5-bromo-1,3-difluoro-2-nitrobenzene (10.0 g, 42.0 mmol, 1.0equiv), KOH (3.1 g, 55.3 mmol, 1.3 equiv) in methanol (100 ml) wasstirred at 40° C. for 3 hrs, then diluted with water (200 ml). Themixture was extracted with ethyl acetate (3×200 ml). The combinedorganic solution was washed with brine, dried and concentrated to yieldthe title compound (11.0 g) as a crude product. ¹HNMR (300 MHz,DMSO-d₆): δ, 7.59 (d, 1H), 7.56 (s, 1H), 3.98 (s, 3H).

Step 1-2, preparation of 5-bromo-3-methoxy-2-nitroaniline: a mixture of5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (11 g, 20.0 mmol), ammoniumhydroxide (30%, 100 ml) in NMP (100 ml) was heated with stirring at 50°C. for 2 days, then cooled to rt, diluted with water (300 ml). Themixture was then extracted with ethyl acetate (3×300 ml). The combinedorganic solution was then washed with brine, dried and concentratedafter the solid was filtered out. The residue was concentrated to yieldthe title compound (10 g) as a yellow solid. MS [M+H]⁺=247.1, 249.1.

Step 1-3, preparation of 5-bromo-3-methoxybenzene-1,2-diamine: a mixtureof 5-bromo-3-methoxy-2-nitroaniline (10 g, 40.5 mmol, 1.0 equiv), NH₄Cl(10.8 g, 201.9 mmol, 5.0 equiv), ethanol (100 ml), water (10 ml) and Fepower (11.4 g, 5.0 equiv) was stirred at 70° C. for 3 hrs. After coolingto rt, the mixture was diluted with ethyl acetate (200 ml) and the solidwas then filtered out. The mixture was then further diluted with water(200 ml). Organic layer was separated and aqueous layer was furtherextracted with ethyl acetate (3×200 ml). The combined organic solutionwas washed with brine, dried and concentrated. The residue was purifiedby silica gel column chromatography, eluted with ethyl acetate/petroleumether to afford the title compound (6.5 g) as an off-white solid. MS[M+H]⁺=217.1, 219.1.

Step 1-4, preparation of tert-butylN-[1-(2-amino-5-bromo-3-formylpyridin-4-yl)piperidin-4-yl]carbamate: amixture of 2-amino-5-bromo-4-chloropyridine-3-carbaldehyde (25.0 g,106.2 mmol, 1.0 equiv), tert-butyl N-(piperidin-4-yl)carbamate (21.2 g,105.9 mmol, 1.0 equiv), TEA (32.1 g, 317.2 mmol, 3.0 equiv),N,N-dimethylformamide (120 mL) was stirred for 2 hrs at 80° C. Thereaction was then quenched by the addition of 500 mL of water. Theresulting solution was extracted with 3×500 mL of dichloromethane andthe organic layers combined. The resulting mixture was washed with 5×200mL of water. The mixture was dried over anhydrous sodium sulfate. Thesolids were filtered out and the liquid concentrated under vacuum. Theresidue was purified via a silica gel column eluted withdichloromethane/ethyl acetate (5:1) to give the title compound as ayellow solid (15 g). MS [M+H]=399.1, 401.1.

Step 1-5, preparation of tert-butylN-{1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl}carbamate:into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-[1-(2-amino-5-bromo-3-formylpyridin-4-yl)piperidin-4-yl]carbamate (5.0g, 12.5 mmol, 1.0 equiv), (3-fluoro-5-methylphenyl)boronic acid (2.9 g,18.8 mmol, 1.5 equiv), Pd₂(dba)₃.HCCl₃ (1.3 g, 1.4 mmol, 0.10 equiv),K₃PO₄ (8.0 g, 37.7 mmol, 3.00 equiv), P(t-Bu)₃.HBF₄ (1.1 g, 0.3 equiv),toluene (50 mL), water (5 mL). The resulting solution was stirred for 2hrs at 70° C., and then was concentrated under vacuum. The residue waschromatographied on a silica gel column eluted with ethylacetate/petroleum ether (1:2) resulting in the title compound as a brownsolid (5.0 g). MS [M+H]=429.2.

H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.02 (s, 1H), 7.87 (s, 1H), 7.65 (br,1H), 7.02 (d, J=9.6 Hz, 1H), 6.96-6.77 (m, 3H), 3.25 (s, 1H), 3.10 (d,J=12.5 Hz, 2H), 2.77 (t, J=11.6 Hz, 2H), 2.38 (s, 3H), 1.65-1.61 (m,2H), 1.44-1.37 (m, 11H).

Step 1-6, preparation of tert-butylN-{1-[2-amino-3-(6-bromo-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate:A mixture of tert-butylN-{1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl}carbamate(5 g, 11.7 mmol), 5-bromo-3-methoxybenzene-1,2-diamine (3.8 g, 17.5mmol, 1.0 equiv), water (5 ml) in DMSO (50 ml) was heated at 120° C. for16 hrs, cooled to rt, and then diluted with water (100 ml). The mixturewas extract with ethyl acetate (3×200 ml). Combined organic solution waswashed with brine, dried over anhydrous Na₂SO₄, filtered and thenconcentrated. The residue was purified by silica gel chromatographyeluted with ethyl acetate/petroleum ether to afford the title compoundas a brown solid (4.2 g). MS [M+H]⁺=625.1, 627.1.

Step 1-7, preparation of tert-butylN-{1-[2-amino-3-(6-cyano-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate:to each of total four microwave tubes, purged and maintained under aninert atmosphere of N₂, tert-butylN-{1-[2-amino-3-(6-bromo-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate(1.1 g, 1.7 mmol), Zn(CN)₂ (600 mg, 5.1 mmol, 3.0 equiv), Pd₂(dba)₃ (53mg, 0.06 mmol, 0.03 equiv),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (105 mg, 0.18 mmol, 0.1equiv) and DMF (10 ml) were added. Each tube was heated in microwave for8 hrs at 120° C., then cooled to rt. The mixture from four tubes werecombined and filtered to remove the solid and then diluted with water.Organics were extracted with ethyl acetate (3×100 ml). The combinedorganic solution was washed with brine, dried and concentrated. Theresidue was purified by RP-HPLC to afford the title compound (2.6 g) asoff-white solid. MS [M+H]⁺=572.6.

Step 1-8, preparation of2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile:a mixture of tert-butylN-{1-[2-amino-3-(6-cyano-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate(80 mg, 0.14 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (2mL) was stirred for 2 hrs at rt and then concentrated, The crude productwas purified by Prep-HPLC according to the following conditions (XBridgePrep C18): Column, 30×100 mm 5 m; mobile phase, Water (0.05% TFA), ACN(26% up to 44% in 6 min); Detector, 220 nm. The fractions contained pureproduct were combined and lyophilized after addition of 1N HCl (0.1 ml),which resulted in the title compound as an off-white solid (HCl salt,41.4 mg). MS [M+H]⁺=472.3. ¹HNMR (300 MHz, CD₃OD, ppm): δ, 7.83 (s, 1H),7.70 (s, 1H), 7.25 (s, 1H), 7.17 (s, 1H), 7.10 (d, J=9.6 Hz, 2H), 4.11(s, 3H), 3.26 (m, 2H), 3.02 (m, 1H), 2.55 (t, J=12.6 Hz, 2H), 2.48 (s,3H), 1.61 (m, 2H), 1.23 (m, 2H).

The following compounds were prepared similarly to Example 1 withappropriate substituting reagents, solvents and substrates at differentsteps and they may require additional functional group modifications onbenzimidazolyl side chain via well known chemistry with appropriatereagents, and different salt such as TFA or formic acid may be obtained.

Compound no. MS (M + H)⁺ 1-2 492.2

Example 2:2-[4-(4-aminopiperidin-1-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile(Compound 1-3)

Step 2-1, preparation of tert-butylN-[1-(2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate: into a40-mL round-bottom flask, was placed 2,4-dichloropyridine-3-carbaldehyde(2.0 g, 11.36 mmol, 1.0 equiv), tert-butyl N-(piperidin-4-yl)carbamate(2.3 g, 11.48 mmol, 1.0 equiv), TEA (3.5 g, 34.59 mmol, 3.0 equiv),N,N-dimethylformamide (10 mL). The resulting solution was stirred for 1h at 40° C. and then quenched with 50 mL water. The crude product wasextracted out by 3×20 mL of ethyl acetate and ethyl acetate layer waswashed with 4×20 mL of brine, then dried over anhydrous sodium sulfate.The solids were filtered out. The resulting mixture was concentrated andpurified by silica gel column chromatography eluted with ethylacetate/petroleum ether (1:3) to afford 3.2 g (83%) of the titlecompound as a yellow solid. MS (M+H)⁺=340.1/342.1.

Step 2-2, preparation of tert-butylN-{1-[2-(dimethylamino)-3-formylpyridin-4-yl]piperidin-4-yl}carbamate:into a 40-mL sealed tube, was placed tert-butylN-[1-(2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate (700 mg,2.06 mmol, 1.0 equiv), tetrahydrofuran/Me₂NH (2 M) (10 mL). Theresulting solution was sealed and stirred for 4 hrs at 70° C. Thereaction mixture was cooled to rt and concentrated under vacuum. Theremaining residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1) resulting in 650 mg (91%) of the titlecompound as a light yellow solid. MS (M+H)⁺=349.2/351.2.

Step 2-3, preparation of tert-butylN-{1-[5-bromo-2-(dimethylamino)-3-formylpyridin-4-yl]piperidin-4-yl}carbamate:to tert-butylN-{1-[2-(dimethylamino)-3-formylpyridin-4-yl]piperidin-4-yl}carbamate(600 mg, 1.72 mmol, 1.0 equiv) in DCM (10 ml), NBS (306 mg, 1.72 mmol,1.0 equiv) was added. The mixture was then stirred at 80° C. for 20 min.It was then cooled to rt, concentrated and purified by silica gel columnchromatography, eluting with ethyl acetate/petroleum ether (⅔) to affordthe title compound as a yellow solid (580 mg). MS (M+H)⁺=427.2/429.2.

Step 2-4, preparation of tert-butylN-[1-[2-(dimethylamino)-5-(3-fluoro-5-methylphenyl}-3-formylpyridin-4-yl]piperidin-4-yl]carbamate:into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-[1-(5-bromo-2-(dimethylamino)-3-formylpyridin-4-yl]piperidin-4-yl]carbamate(550 mg, 1.29 mmol), (3-fluoro-5-methylphenyl)boronic acid (396 mg. 2.57mmol, 2.0 equiv), Pd₂(dba)₃ (25 mg, 0.03 mmol. 0.02 equiv), P(t-Bu)₃ (50mg), K₃PO₄ (817 mg, 3.85 mmol, 3.0 equiv), toluene (10 ml), water (1mL). The resulting solution was stirred for 30 min at 70° C. Thereaction mixture was cooled to rt, concentrated. The residue waschromatagraphied onto a silica gel column eluted with ethylacetate/petroleum ether (1:1) to afford the title compound (560 mg) as ayellow solid. MS (M+H)⁺=457.3.

Step 2-5, preparation of tert-butylN-{1-[3-(6-bromo-4-methoxy-1H-1,3-benzodiazol-2-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate:into a 10 ml sealed tube, was placed tert-butylN-[1-[2-(dimethylamino)-5-(3-fluoro-5-methylphenyl}-3-formylpyridin-4-yl]piperidin-4-yl]carbamate(150 mg, 0.33 mol), 5-bromo-3-methoxybenzene-1,2-diamine (142 mg, 0.65mmol, 2.0 equiv), NMP (2 ml), Na₂S₂O₅ (125 mg, 2.0 equiv). The mixturewas sealed and heated with stirring at 120° C. for 8 hrs. After it wascooled to rt, water (50 ml) was added. The mixture was then extractedwith ethyl acetate (3×50 ml). The combined organic layer was washed withwater, brine and dried over anhydrous sodium sulfate. After filtration,the solution was concentrated and purified by silica gel chromatographyeluted with ethyl acetate/petroleum ether (1/1) to afford the titlecompound (160 mg) as a brown solid. MS (M+H)⁺=653.2, 655.2.

Step 2-6, preparation of tert-butylN-{1-[3-(6-cyano-4-methoxy-1H-1,3-benzodiazol-2-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate:into a 10-mL microwave tube purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-{1-[3-(6-bromo-4-methoxy-1H-1,3-benzodiazol-2-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate(150 mg, 0.23 mmol), Xantphos (30 mg, 0.05 mmol. 0.23 equiv), Pd₂(dba)₃(15 mg), DMF (2 mL), Zn(CN)₂ (75 mg, 3.0 equiv). The reaction mixturewas irradiated with microwave radiation for 2 hrs at 140° C. Aftercooled to rt, the mixture was diluted with water (50 ml). The resultingsolution was extracted with ethyl acetate (3×50 ml). The organic layerswere combined and washed with brine, then dried over anhydrous sodiumsulfate. After the solids were filtered out, the solution wasconcentrated and the residue was chromatagrphied by a silica gel columneluted with ethyl acetate/petroleum ether (1/1) to afford the titlecompound as a brown solid (90 mg). MS (M+H)⁺=600.2.

Step 2-7, preparation of2-[4-(4-aminopiperidin-1-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile:a mixture of tert-butylN-{1-[3-(6-cyano-4-methoxy-1H-1,3-benzodiazol-2-yl)-2-(dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate(90 mg, 0.15 mmol), TFA (1 ml) in DCM (5 ml) was stirred at rt for 2hrs. The mixture was concentrated and yielded the title compound as anoff-white solid (84.1 mg). MS (M+H)⁺=500.3.

Example 3:4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carbonitrile(Compound 2-2)

Step 3-1, preparation of tert-butylN-[1-(5-bromo-2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate: amixture of tert-butylN-[1-(2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate (500 mg,1.47 mmol, Step 2-1) and NBS (290 mg, 1.63 mmol, 1.1 equiv) in DMF (10ml) was stirred at rt for 16 hrs. The mixture was diluted with water(100 ml), and crude was extracted with ethyl acetate (3×100 ml). Theorganics were washed with brine, dried, and then concentrated. The crudewas then purified by a silica gel column chromatography, elute withethyl acetate/petroleum ether (2:3) to afford the title compound as ayellow solid (300 mg). MS [M+H]⁺=418.2/420.1.

Step 3-2, preparation of tert-butylN-[1-[2-chloro-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl]carbamate:Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-[1-(5-bromo-2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate(250 mg, 0.60 mmol), (3-fluoro-5-methylphenyl)boronic acid (92 mg, 0.60mmol, 1.0 equiv), Pd(dppf)Cl₂ (50 mg, 0.07 mmol, 0.12 equiv), K₂CO₃ (165mg, 1.2 mmol, 2.0 equiv), dioxane (5 mL), H₂O (0.5 mL). The resultingmixture was stirred for 2 hrs at 60° C. and then concentrated undervacuum. The residue was chromatographied on a silica gel column, elutedwith ethyl acetate/petroleum ether to produce the title compound as ayellow solid (250 mg). MS [M+H]⁺=448.1.

Step 3-3, preparation of tert-butylN-{1-[2-chloro-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate:using tert-butylN-[1-[2-chloro-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl]carbamate(230 mg, 0.51 mmol), 5-fluoro-3-methoxybenzene-1,2-diamine (160 mg, 1.02mmol, 2.0 equiv), Na₂S₂O₅ (196 mg, 1.03 mmol, 2.0 equiv) in DMSO (5 mL),the title compound was obtained according to procedure described in Step1-5 as a yellow solid (220 mg). MS [M+H]⁺=584.1.

Step 3-4, preparation of methyl4-(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxylate:into a pressure vessel (50 ml), purged and maintained with an inertatmosphere of CO (10 atm), was tert-butylN-{1-[2-chloro-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate(180 mg, 0.31 mmol), Pd(dppf)Cl₂ (18 mg, 0.02 mmol), TEA (94 mg, 0.93mmol), MeOH (15 mL). The resulting mixture was stirred for 8 hrs at 120°C., cooled to rt and concentrated. The residue was purified via a silicagel column, eluted with ethyl acetate/petroleum ether (5:4) to give thetitle compound as a light yellow solid (160 mg). MS [M+H]⁺=608.5.

Step 3-5, preparation of tert-butylN-{1-[2-carbamoyl-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate:into a 40-mL sealed tube, was placed methyl4-(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxylate(150 mg, 0.25 mmol), MeOH/NH₃ (10 mL, 7 mol/L). The resulting solutionwas stirred for 5 hrs at 80° C., then concentrated resulting in thetitle compound as a brown solid (140 mg). MS [M+H]⁺=593.1.

Step 3-6, preparation of tert-butylN-{1-[2-cyano-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate:into a 8-mL round-bottom flask, was placed tert-butylN-{1-[2-carbamoyl-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate(20 mg, 0.03 mmol), TEA (10 mg, 0.10 mmol, 3.3 equiv), DCM (1 mL),trifluoroacetic anhydride (14 mg, 0.07 mmol, 2.3 equiv). The resultingsolution was stirred for 2 hrs at rt, and then concentrated. The crudewas purified by Prep-HPLC to yield the title compound as off-white solid(10 mg). MS [M+H]⁺=575.3.

Step 3-7, preparation of4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carbonitrile:into a 100-mL round-bottom flask, was placed yield tert-butylN-{1-[2-cyano-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate(10 mg, 0.02 mmol), DCM (5 mL), TFA (1 mL). The resulting solution wasstirred for 2 hrs at rt and then concentrated. The residue was dilutedwith water (5 mL) and CH₃CN (1 mL) and then lyophilized to yield thetitle compound as TFA salt (off-white solid, 7.8 mg). MS [M+H]⁺=475.2.¹HNMR (300 MHz, CD₃OD): δ, 8.47 (s, 1H), 7.19-7.08 (m, 3H), 7.02-6.99(m, 2H), 6.85-6.73 (m, 2H), 4.05 (s, 3H), 3.3.21-3.12 (m, 2H), 2.94-2.92(m, 1H), 2.59-2.42 (m, 5H), 1.64-1.54 (m, 2H), 1.25-1.19 (m, 2H).

Example 4:4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxamide(Compound 2-3)

Step 4-1: Preparation of4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxamide:a mixture of tert-butylN-{1-[2-carbamoyl-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate(20 mg, 0.04 mmol, Step 3-5), DCM (5 mL) and TFA (1 mL) was stirred for2 hrs at rt and concentrated. The crude product was purified byPrep-HPLC to afford the title compound as an off-white solid (TFA salt,6.7 mg). MS [M+H]⁺=493.2. ¹HNMR (300 MHz, CD₃OD): δ, 8.56 (s, 1H),7.13-7.06 (m, 4H), 6.90 (d, J=11.7 Hz, 1H), 4.06 (s, 3H), 3.18-3.08 (m,2H), 2.87-2.80 (m, 1H), 2.48-2.42 (m, 5H), 1.63-1.60 (m, 2H), 1.04-0.99(m, 2H).

Example 5: methyl4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxylate(Compound 2-1)

Step 5-1: Preparation of methyl4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxylate:a mixture of methyl4-(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxylatefrom Step 3-4 (20 mg) in TFA/DCM (1 ml, 1:1) for 1 h and concentrated.The crude was purified by RP HPLC to afford the title compound (13.7 mg)as an off-white solid. MS [M+H]⁺=508.2.

Example 6:2-{4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-2-amino-5-(3-fluoro-5-methylphenyl)pyridin-3-yl}-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile(Compound 3-16)

Step 6-1, preparation of2-amino-5-bromo-4-chloropyridine-3-carbaldehyde: into a 1 L round-bottomflask, was placed tert-butyl N-(4-chloro-3-formylpyridin-2-yl)carbamate(30.0 g, 117 mmol, 1.00 equiv), DCE (400 mL), NBS (42.0 g, 236 mmol, 2.0equiv). The resulting solution was stirred for 16 hrs at 80° C. and thenconcentrated under vacuum. The residue was stirred with 200 mL of ethylacetate to form a precipitate. The precipitated solids were thencollected by filtration and dried in an oven under reduced pressureresulting in the title compound as a red solid (17.0 g). MS[M+H]⁺=236.9.

Step 6-2, preparation of benzyl (4αS,8αS)6-(2-amino-5-bromo-3-formyl-pyridin-4-yl)-octahydro-pyrido[3,4-b][1,4]oxazine-1-carboxylate:into a 100-mL round-bottom flask, was placed2-amino-5-bromo-4-chloropyridine-3-carbaldehyde (2 g, 8.5 mmol, 1.5equiv), benzyl(4αS,8αS)-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (1.57 g,5.7 mmol, 1.0 equiv), TEA (1.72 g, 17.00 mmol, 3.0 equiv),N,N-dimethylformamide (20 mL). The resulting solution was stirredovernight at 80° C., then cooled to rt and diluted with water (50 ml).The mixture was extracted with ethyl acetate (3×100 ml) and the organiclayers combined, washed with brine (3×100 ml) and then concentratedunder vacuum which resulted in the title compound as a yellow solid (1.2g). MS [M+H]⁺=475.1.

Step 6-3, preparation of benzyl(4αS,8αS)-6-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate:into a 50-mL 3-necked round-bottom flask purged and maintained withnitrogen, was placed benzyl(4αS,8αS)-6-(2-amino-5-bromo-3-formylpyridin-4-yl)-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate(300 mg, 0.63 mmol, 1.0 equiv), (3-fluoro-5-methylphenyl)boronic acid(192 mg, 1.25 mmol, 2.0 equiv), Pd₂(dba)₃. CHCl₃ (65 mg, 0.06 mmol, 0.10equiv), P(t-Bu)₃.HBF₄ (37 mg, 0.13 mmol, 0.2 equiv), toluene (3 mL),water (0.3 mL), K₃PO₄ (402 mg, 3.0 equiv). The resulting mixture wasstirred for 2 hrs at 70° C., and concentrated under vacuum after coolingto rt. The residue was chromatographied by a silica gel column elutedwith ethyl acetate/petroleum ether to give the title compound as ayellow solid (200 mg). MS [M+H]⁺=505.2.

Step 6-4, preparation of benzyl(4αS,8αS)-6-[2-amino-3-(6-bromo-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate:into a 50-mL round-bottom flask, was placed benzyl(4αS,8αS)-6-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate(100 mg, 0.20 mmol, 1.00 equiv), 5-bromo-3-methoxybenzene-1,2-diamine(65 mg, 0.30 mmol, 1.50 equiv), Na₂S₂O₅ (75 mg, 0.39 mmol, 2.00 equiv),DMSO (2 mL). The resulting mixture was stirred for 16 hrs at 100° C.,then cooled to rt and diluted with water (50 ml). The mixture wasextracted with ethyl acetate (3×50 ml) and the organic layers combinedand washed with brine (3×50 ml), and then concentrated under vacuum. Theresidue was chromatographied by a silica gel column eluted with ethylacetate/petroleum ether to give the title compound (120 mg) as a yellowsolid. MS [M+H]⁺=701.2.

Step 6-5, preparation of benzyl(4αS,8αS)-6-[2-amino-3-(6-cyano-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate:into a 10-mL vial purged and maintained with nitrogen, was placed benzyl(4αS,8αS)-6-[2-amino-3-(6-bromo-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate(120 mg, 0.17 mmol, 1.00 equiv), N,N-dimethylformamide (2 mL), Pd₂(dba)₃(18 mg, 0.02 mmol, 0.10 equiv), Xantphos (20 mg, 0.03 mmol, 0.20 equiv),zinc dicarbonitrile (40 mg, 0.34 mmol, 2.00 equiv). The mixture wasirradiated with microwave radiation for 2 hrs at 120° C., then cooled tort and diluted with water (5 ml). The crude was extracted with ethylacetate (3×50 ml). The organic layers were combined, washed with brine(3×50 ml) and concentrated under vacuum. The residue was purified by asilica gel column chromatography eluted with ethyl acetate/petroleumether to give the title compound (70 mg) as yellow oil. MS [M+H]⁺=648.3.

Step 6-6, preparation of 2-[4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-2-amino-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-methoxy-1H-1,3-benzodiazole-6-carbonitrile:a mixture of benzyl (4αS,8αS)-6-[2-amino-3-(6-cyano-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate(70 mg, 0.11 mmol, 1.00 equiv), trifluoroacetic acid (2 mL) was stirredfor 3 hrs at 60° C. The reaction mixture was cooled to rt. The resultingmixture was concentrated under vacuum. The residue was dissolved in DMF(4 mL) and further purified by Prep-HPLC to give the title compound astrifluoroacetic acid salt (49.6 mg, a white solid). MS [M+H]⁺=514.4.¹HNMR (300 MHz, CD₃OD): δ, 7.83 (s, 1H), 7.72 (s, 1H), 7.25 (s, 1H),7.15-7.07 (m, 3H), 4.10 (s, 3H), 3.96-3.87 (m, 1H), 3.62-3.48 (m, 1H),3.41-3.35 (m, 1H), 3.26-3.05 (m, 4H), 2.93-2.85 (m, 1H), 2.65-2.55 (m,1H), 2.48 (s, 3H), 2.33-2.26 (m, 1H), 1.59-1.56 (m, 1H), 1.31-1.19 (m,1H).

The following compounds were prepared similarly to Example 6 withappropriate substituting reagents and substrates at different steps orwithout the step that converting bromo group to cyano group:

Compound No. MS (M + H)⁺ 3-1  495.2 3-2  499.2 3-3  481.2 3-6  513.23-7  515.2 3-8  511.3 3-9  493.2 3-10 507.3 3-11 500.3 3-12 514.3 3-13541.3 3-14 507.3 3-15 521.3 3-17 527.1 3-18 518.2 3-19 506.2

Example A-1: Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 1-100 mg of awater-soluble salt of a compound Formula (I), Formula (II), or Formula(III), or a pharmaceutically acceptable salt or solvate thereof, isdissolved in sterile water and then mixed with 10 mL of 0.9% sterilesaline. A suitable buffer is optionally added as well as optional acidor base to adjust the pH. The mixture is incorporated into a dosage unitform suitable for administration by injection Example A-2: Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficientamount of a compound of Formula (I), Formula (II), or Formula (III), ora pharmaceutically acceptable salt thereof, is added to water (withoptional solubilizer(s), optional buffer(s) and taste maskingexcipients) to provide a 20 mg/mL solution.

Example A-3: Oral Tablet

A tablet is prepared by mixing 20-50% by weight of a compound of Formula(I), Formula (II), or Formula (III), or a pharmaceutically acceptablesalt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% byweight of low-substituted hydroxypropyl cellulose, and 1-10% by weightof magnesium stearate or other appropriate excipients. Tablets areprepared by direct compression. The total weight of the compressedtablets is maintained at 100-500 mg.

Example A-4: Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg ofa compound of Formula (I), Formula (II), or Formula (III), or apharmaceutically acceptable salt thereof, is mixed with starch or othersuitable powder blend. The mixture is incorporated into an oral dosageunit such as a hard gelatin capsule, which is suitable for oraladministration.

In another embodiment, 10-500 mg of a compound of Formula (I), Formula(II), or Formula (III), or a pharmaceutically acceptable salt thereof,is placed into Size 4 capsule, or size 1 capsule (hypromellose or hardgelatin) and the capsule is closed.

Example A-5: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compound ofFormula (I), Formula (II), or Formula (III), or a pharmaceuticallyacceptable salt thereof, is mixed with hydroxypropyl celluose, propyleneglycol, isopropyl myristate and purified alcohol USP. The resulting gelmixture is then incorporated into containers, such as tubes, which aresuitable for topical administration.

Example B: SSTR Assays

Membrane Preparation

Crude membrane fractions are prepared from Chinese hamster ovary (CHO)cells stably expressing one of the five human or rodent somatostatinreceptor subtypes. The cells are grown to 85-100% confluence on standardtissue culture dishes in DM-MEM growth media (Gibco) with followingadditives: 10% fetal bovine serum (Gibco), 100 U/mL penicillin (Gibco),100 ug/mL streptomycin (Gibco), 10 mM HEPES (Gibco), 0.5 mg/mL G-418(Gibco). To prepare membranes, cells are washed once with 1× Dulbecco'sphosphate buffered saline (Gibco) containing 10 mM HEPES (Gibco) thenonce with sodium free binding buffer (50 mM Tris Base, 5 mM MgCl₂-6H₂0and 1 mM EGTA adjusted to pH 7.8). The cells are then scraped intobinding buffer containing a protease inhibitor cocktail (100 ug/mLpepstatin A (Sigma), 50 ug/mL leupeptin (Sigma), 25 ug/mL aprotinin(Sigma) and 10 mg/mL Bacitracin (USB Corporation)). The cells arecentrifuged at 43,500×g, homogenized, and the resulting membranes arecollected by centrifugation at 67,000×g. The membranes are thenresuspended in binding buffer containing the protease inhibitor cocktailusing a glass dounce homogenizer.

Functional Assay for SSTR2 Agonists

General overview: All five SSTR subtypes are Gi coupled G-proteincoupled receptors (GPCRs) that lead to decreases in intracellular cyclicAMP (cAMP) when activated by an agonist. Therefore, measurement ofintracellular cAMP levels can be used to assess whether compounds of theinvention are agonists of SSTR subtypes (John Kelly, Troy Stevens, W.Joseph Thompson, and Roland Seifert, Current Protocols in Pharmacology,2005, 2.2.1-2.2). One example of an intracellular cAMP assay isdescribed below.

cAMP Assay Protocol

Four days prior to the assay, 5,000 Chinese hamster ovary cells (CHO-K1,ATCC #CCL-61) stably expressing the human somatostatin receptor subtype2 are plated in each well of a 96-well tissue culture-treated plate inHam's F12 growth media (ThermoFisher #10-080-CM) supplemented with 10%donor bovine serum (Gemini Bio-Products #100-506), 100 U/mL penicillin;100 ug/mL streptomycin; 2 mM L-glutamine (Gemini Bio-Products #400-110)and 0.2 mg/mL hygromycin B (GoldBio #31282-04-9). The cells are culturedat 37° C., 5% CO₂ and 95% humidity. On the day of the assay, the mediais aspirated and the cells are treated with 50 μL of 1.6 μM NKH477(Sigma #N3290) plus various dilutions of compounds of the invention inassay buffer [1× Hank's Balanced Salt Solution (ThermoFisher#SH3058802), 0.5 mM HEPES pH 7.4, 0.1% bovine serum albumin, 0.2 mM3-Isobutyl-1-methylxanthine (IBMX, VWR #200002-790)]. The cells areincubated for 20 minutes at 37° C. (the final concentration of thecompounds of the invention are typically 0-10,000 nM). The cells aretreated with 50 μL of lysis buffer (HRTF cAMP kit, Cisbio). The lysateis transferred to 384-well plates and cAMP detection and visualizationantibodies are added and incubated for 1-24 hours at room temperature.The time-resolved fluorescent signal is read with a Tecan M1000Promultiplate reader. The intracellular cAMP concentrations are calculatedby regression to a standard curve and are plotted vs. the concentrationof the compounds of the invention and the EC₅₀ of the compounds arecalculated using standard methods. All data manipulations are inGraphPad Prism v6.

Illustrative biological activity of compounds is demonstrated in thefollowing Table (Table A) by evaluating the inhibition of cAMPactivities via human SST2 receptor (SSTR2):

TABLE A Cpd No. EC₅₀ 1-1  A 1-2  B 1-3  C 2-1  B 2-2  B 2-3  B 3-1  A3-2  B 3-3  B 3-6  B 3-7  A 3-8  A 3-9  B 3-10 B 3-11 B 3-12 C 3-13 B3-14 A 3-15 A 3-16 A 3-17 A 3-18 B 3-19 B A = EC₅₀ < 0.1 nM; B = EC₅₀between ≥0.1 nM and <1 nM; C = EC₅₀ ≥ 1 nM

The following Table (Table B) demonstrates improved selectivity ofexemplary compounds for inhibition of cAMP via hSSTR2 vs. hSSTR4.

TABLE B

Cpd hSST4/hSST2 No. R¹ R⁶ (ratio) H CN d 1-1 NH₂ CN a H F f 2-1 CO₂Me Fd 2-2 CN F e 2-3 CONH₂ F b a = above 50, b = between 15 and 50; c =between 2.5 and 15; d = between 1 and 2.5; e = between 1 and 0.5; f =below 0.5.

The following Table (Table C) further demonstrates improved selectivityfor inhibition of cAMP via hSSTR2 vs. hSSTR4 of additional exemplarycompounds.

TABLE C

Cpd hSST4/hSST2 No. R¹ R⁶ R⁷ R⁹ (ratio) H F F H f 3-3 NH₂ F F H c H OMeF H f 3-9 NH₂ OMe F H c 3-10 CH₃NH— OMe F H a H OMe CN H d 3-11 NH₂ OMeCN H a 3-12 CH₃NH— OMe CN H a H OMe F Cl d 3-17 NH2 OMe F Cl c 3-13CH₃NH— OMe F Cl a H OMe CN F d 3-18 NH₂ OMe CN F b H F CN F d 3-19 NH₂ FCN F b a = above 50, b = between 15 and 50; c = between 2.5 and 15; d =between 1 and 2.5; e = between 1 and 0.5; f = below 0.5

Example C: Liver Microsomal Stability Assay Protocol

The in vitro stabilities of compounds of interest were determined forvarious species using pooled male and female human, pooled maleSprague-Dawley rat, pooled male Cynomolgus monkey, and pooled maleBeagle dog liver microsomes at microsomal protein concentrations of 0.5mg/mL. Incubations were carried out in a potassium phosphate buffer (50mM). The NADPH-generating system was composed of NADP+ (1 mM), magnesiumchloride (3 mM), EDTA (1 mM), glucose-6-phosphate (5 mM) andglucose-6-phosphate dehydrogenase (1 Unit/mL) for all experiments.Compounds of interest in DMSO were added to achieve a final incubationconcentration of 1 μM (final DMSO content was 0.1% v/v and finalacetonitrile content was 0.9%). The final incubation volume was 400 μL.Incubations were conducted at 37° C. for 0, 5, 10, 20, 40 and 60 minutesin a shaking water bath and terminated by removing 50 μL of incubationmixture and adding to 100 μL of ice cold acetonitrile containinginternal standard. Following precipitation by centrifugation at 3500 rpmand 4° C. for 30 minutes, compounds of interest and internal standardwere analyzed in the resultant supernatant using a multiple reactionmonitoring (MRM) LC-MS/MS method. MS conditions were optimized for eachanalyte. Depletion rates of compounds of interest were measured andhalf-life, scaled intrinsic clearance, and predicted scaled systemicclearance calculations were made using this data.

The following Table (Table D) illustrates human liver microsomalstability of exemplary compounds.

TABLE D

Cpd No. R¹ R⁶ R⁷ R⁹ HLM t1/2 (min) H F F H 41 3-3 NH₂ F F H 231 H OMe CNH 115 3-11 NH₂ OMe CN H >693 H OMe CN F 58 3-18 NH₂ OMe CN F 99 H F CN F144 3-19 NH₂ F CN F 347

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A method of suppressing secretion of growthhormone (GH), insulin, glucagon, insulin-like growth factor 1 (IGF-1),prolactin, or combinations thereof, in a mammal comprising administeringto the mammal in need thereof a therapeutically effective amount of acompound that has one of the following structures:

or a pharmaceutically acceptable salt or solvate thereof.
 2. The methodof claim 1, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 3. The methodof claim 1, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 4. The methodof claim 1, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 5. The methodof claim 1, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 6. The methodof claim 1, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 7. The methodof claim 1, wherein the mammal is a human.
 8. The method of claim 1,wherein the mammal is a dog or cat.
 9. A method for modulatingsomatostatin receptor subtype 2 (SSTR2) activity in a mammal comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound that has one of the following structures:

or a pharmaceutically acceptable salt or solvate thereof.
 10. The methodof claim 9, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 11. Themethod of claim 9, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 12. Themethod of claim 9, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 13. Themethod of claim 9, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 14. Themethod of claim 9, wherein the compound has the following structure:

or a pharmaceutically acceptable salt, or solvate thereof.
 15. Themethod of claim 9, wherein the mammal is a human.
 16. The method ofclaim 9, wherein the mammal is a dog or cat.